C. AT1 receptor expression in Cervical cancer patients

Expression of AT1 receptor in normal and neoplastic tissues was measured by immunohistochemistry by Kikkara et al in their study of Cervical cancer patients (Kikkawa et al, 2004). Mean staining intensity level was stronger in invasive carcinoma cells than in normal dysplasia, and carcinoma in situ tissues. Ang II induced the secretion of VEGF from Siha cells and promoted their invasive potential.

Laio et al (Liao et al, 2007) have also obtained similar conclusions to Kikkara et al (2004), in another study, where the clinical significance of AT1 was investigated in cervical cancer progression. AT1 mRNA expression was examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in

paraffin-embedded tissues from 35 cases of cervical squamous cell carcinoma, 15 cases of cervical intraepithelial neoplasia, and 15 cases of normal cervix. The rate of AT1 expression mRNA was 77.1%, 40.0% and 0, respectively, in squamous cell carcinomas, cervical intraepithelial neoplasia and normal cervical tissues, while their mRNA quantities were 0.3863 +/- 0.041, 0.0768 +/- 0.035 and 0, respectively. There was a statistically significant difference between them (P < 0.01). The average staining intensity of AT1 protein was found to be stronger in invasive carcinoma cells than that in dysplasia tissues and normal ones (P < 0.01).

D. AT1 receptor expression in Brain cancer patients

In 133 tumours from patients with astrocytoma (Arrieta et al, 2008), 10% of low-grade astrocytomas were found to be positive for AT1, whereas grade III and IV astrocytomas were positive in 67% (P<0.001). AT1-positive tumours showed higher cellular proliferation and vascular density and had a lower survival rate than those with AT1-negative (P<0.001). Patients with AT1 receptor positive had less survival compared to the negative ones, 9.5 months versus 16.5 months. AT1 expression also correlated with increased expression of VEGF and PDGF.

E. AT1 receptor expression in Pancreatic cancer patients

In 19 of the 25-neoplastic tissues examined in patients (approximately 75%), ACE and AT1 mRNA and protein levels were significantly upregulated when compared to healthy tissue (Shibata et al, 2005). ACE/AT1-negative tumours were found in only 2 cases (8%). VEGF expression was significantly higher in the tissues that expressed high levels of AT1 and ACE and these were co-localized in the malignant ducts and the surrounding tissue.

F. AT1 receptor expression in Endometrial cancer patients

In 94 cases, a positive correlation between Ang II expression and surgical stage (p = 0.01) was found (Shibata et al, 2005). Of the 94 cases, 56 (59.6%) expressed AT1 and 73 (77.7%) VEGF. The presence of Ang II and AT1 expression was associated with a significantly poorer prognosis.

G. Mouse model confirms the role of both host and tumour derived AT1 in the progression of disease

Using a mouse model of Lewis lung carcinoma (a mouse derived experimental transportable lung carcinoma also known as 3LL or LLC) (Imai et al, 2007), the study concluded that the growth of the cancer in mice lacking AT1 was significantly impaired in comparison to wild-type mice and that associated VEGF expression and angiogenesis was reduced. In the AT1 knock out mice (those that lacked the genes for AT1), tumour derived AT1 expression (the tumour still having the genes for AT1) still occurred, although to a lesser degree, and administration of Candesartan showed further reductions of tumour growth.

The key message from this study is that AT1 derived, both in the surrounding host tissue and in the cancer cells, is important for the progression of the tumour.

H. ACE Inhibitor reduces tumour growth in a mouse model

In another mouse model using implanted cancer forming LNM35 human lung cells (Attoub et al, 2008), treatment with ACE Inhibitor Captopril (2.8 mg/mouse) for 3 weeks resulted in a remarkable reduction of tumour growth (58%, P < 0.01) and lymph node metastasis (50%, P= 0.088). There were no undesirable effects of Captopril treatment on animal behaviour and body weight.

I. Candesartan dramatically reduces cancer metastasis in a mouse model

The protective effects of Candesartan, an AT1 antagonist, (10 mg/kg) in a 16-day mouse renal cancer lung metastasis model have been demonstrated by Miyajima et al (2002). In the model, metastases to the lung showed prominent AT1 expression and Candesartan treatment dramatically prevented the formation of additional nodules (14.9 ± 1.8; P < 0.0001; n = 12) compared with control metastatic mice (123.3 ± 8.6; n = 13). It was noted that the use of Candesartan also resulted in the inhibition of VEGF expression and neovascularization.

IV. AT1, the pathway to the Injury Response

The question that then arises is why should manipulation of the Angiotensin system have such a profound effect on the progression of tumours. If one was to consider that the mechanism might be anti-inflammatory, then the answer suggests that blockade of AT1 leads to a fundamental change in the mechanism of the disease and not merely tinkering with one component.

In ‘Atherosclerosis - an inflammatory disease’ the seminal work by Russell Ross that explained an injury response as the cause of this disease, he also explained that the cellular interactions in atherogenesis are fundamentally no different from those in chronic inflammatory fibroproliferative diseases such as cirrhosis, rheumatoid arthritis, glomerulosclerosis, pulmonary fibrosis, and chronic pancreatitis (Ross, 1999). Additionally Ross et al in their review of atherosclerosis and cancer suggest that there are common molecular pathways of disease development and progression in these diseases (Ross et al, 2001). They conclude that a series of molecular pathways of disease development and progression are also common to atherosclerosis and cancer; that the world's two most common diseases are far more closely aligned than previously believed and that emerging anti-inflammatory and antiproliferative therapeutic strategies may ultimately be efficacious in both conditions.

The role and benefits of Angiotensin Receptor Blockade in the treatment of Cardiovascular disease and Atherosclerosis is now widely accepted. Furthermore, the mechanism of not just how, but also, more importantly, why is now understood.

TGF-beta, a powerful cytokine commonly found in blood plasma, has important regulation, inflammation, healing and repair functions. The ability of TGF-Beta to suppress carcinogenesis is recognised to be of great importance; however, tumour cells do ultimately evolve to avoid its growth inhibitory and apoptotic effects. Malignant tumours themselves express TGF-beta to their advantage, promoting angiogenesis, the remodelling and destruction of surrounding healthy tissue, and also immune suppression. Efforts through journal literature review to discover the means by which cancers are able to generate TGF-beta, allowed the authors to conclude that it was in fact through increased extracellular presentation of Angiotensin II Type 1 receptor (Smith and Missailidis, 2004). AT1 expression is an endemic reaction by all cells that are under stress: hypoxia (Krick et al, 2005), sheer stress (Yasuda et al, 2008; Hitomi et al, 2006; Delli et al, 2008) and oxidative stress via oxidized LDL acting on the LOX-1 receptor (Watanabe et al, 2001; Li et al, 1999; Kickenig et al, 1997; Hu et al, 2008). The expression and activation of AT1 receptors is thus coordinating a stress (or injury/wound) response (

Figure 6) (Smith, 2008).

In addition to the mediators reviewed by Smith and Missailidis (2004) and Suzuki et al (2003), a full spectrum of important molecules involved in the cellular response to stress are induced by the AT1 receptor (Figure ). These include the pro-inflammatory mediators Interleukin-1 beta (IL-1b), tumour Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), in addition to many other agents that promote the influx and migration of immune and inflammatory cells, the growth of new blood vessels (notably VEGF) and tissue remodelling (notably Matrix Metalloproteinases and Transforming Growth Factor-Beta (TGF-B)).

With the role of AT1 in cancer and cardiovascular disease established, when the literature of other diseases is reviewed, it is reasonable to anticipate that the role of this receptor is system-wide with regard to chronic inflammation and injury. Fortunately, interest in the wider implications of the AT1 receptor within disease is increasing and these studies together, summarised in Table 1, further substantiate its systemic role.

Searches across the literature for ACE gene polymorphisms also substantiate this relationship with disease and injury, with a positive correlation found in Alzheimer’s disease (Yand and Liu, 2008), Rheumatoid Arthritis (Uppal et al, 2007), Parkinson’s (Lin et al, 2002), Tuberculosis (Ogarkov et al, 2008), Lupus (Rabbani et al, 2008), Sarcoidosis (Tahir et al, 2007), COPD (Busquets et al, 2007), Asthma (Gao et al, 2000), Ulcerative colitis (but not Crohn’s) (Saibeni et al, 2007), Myalgic Encephalomyelitis (Chronic Fatigue Syndrome) (Vladutiu and Natelson, 2004), Depression (Bondy et al, 2005), suicidal behaviours (Sparks et al, 2009), late respiratory complications of mustard gas exposure (Hosseini-Khalili et al, 2008), long term effects of radiation poisoning (Kehoe et al, 2009), and Type II Diabetes (Ramachandran et al, 2008). Some inflammatory diseases, such as Crohn’s, appear neutral with respect to ACE polymorphism. However, this may be due to the presence and activity of the AT2 receptor or wider aspects of the Angiotensin System that still require further exploration (such as the ACE2 and Ang pathways (Kaufman, 1987; Health News, 2008; Shafiq et al, 2005; Hohn Hopkins Medical Letters, 2002; Athyros et al, 2009; Veillard and Mach, 2002; Cuatrecasas et al, 2006).

D. Adaptive Process: The Immune Response

The adaptive immune response is driven by antigen presentation and this process has been well described (Reis e Sousa, 2004). The host's cells express "self" antigens. These antigens are different from those on the surface of bacteria or on the surface of virally infected host cells or cancer cells.

With the exception of non-nucleated cells (including erythrocytes), all cells are capable of presenting antigen and of activating the adaptive response. Some cells are specially equipped to present antigen, and to prime naive T cells. Dendritic cells and B-cells (and to a lesser extent macrophages) are equipped with special immunostimulatory receptors that allow for enhanced activation of T cells, and are termed professional antigen presenting cells (APC).

A key step in the adaptive immune response is conditioning or maturing of the APC, where it develops the ability to communicate the antigen to T Cells in the lymph nodes. Several T cell subgroups can be activated by professional APCs, and each type of T cell is specially equipped to deal with each unique toxin or bacterial and viral pathogen. The type of T cell activated, and the type of response generated depends, in part, on the context in which the APC first encountered the antigen. Many cytokines have pleiotropic properties that steer either the early (innate) or adaptive (antigen derived) response. Notably, IL-4 is associated with TH2 phenotype and B cell activity, IFN-a with TH1 and macrophages, IL-17 with TH17 (Iwakura et al, 2008) and IL-12 with TH0 and CD8. Commonly IL-2 is regarded as having an overarching presence in supporting immune cell population and function, be they ‘inflammatory’ or ‘regulatory’ (Hoyer et al, 2008), whilst IL-10 is generally seen as having an overarching suppressive role.

Within this complexity, IL-2 is postulated as the key candidate accelerator of the Adaptive Immune Response, having a significant effect on the progression of the Dendritic Cell lifecycle (Granucci et al, 2003), and IL-10 is proposed as the brake due to its very broad role in regulation (Mocellin et al, 2004; Schneider et al, 2004). Of particular interest is the relationship between dendritic cells and regulatory T cells (Mahnke et al, 2007). Only mature/activated dendritic cells stimulate T cell proliferation, and vice versa, T Regulatory cells are able to affect dendritic cell development, preventing maturation and inducing IL-10. Interestingly, major injury has been reported to induce increased production of interleukin-10 and decreased levels of IL-2 by cells of the immune system, with a negative impact on resistance to infection (Lyons et al, 1997; Miller et al, 2007). The majority of studies also indicate that burn, injury and trauma all reduce the presence of capable dendritic cells as well as cause immune suppression (Muthy et al, 2008; D’Arpa et al, 2009).

VIII. Failure modes in the System: Disease States

With this three-dimensional framework in place, the categorisation of diseases at the extremes of these vectors is now considered.

A. Disease State: Chronic Wound Response

The extreme of the wound response lies in the domain of ‘wounds that will not heal’.

The type of inflammation associated with cancer-induced wounding is clearly immunosuppressive and many bacteria, fungal and parasitic infections similarly promote wounding as a means of immune suppression. Infection is a recognised risk and progressive factor in cardiovascular disease (Ben-Haim et al, 2009). Suspicion and speculation has also been long ongoing regarding infectious components to many diseases whose causes have been attributed to genetics, failure of the immune system or even psychological causes on the part of the patient. This model may serve as a more logical explanation for autoimmune diseases (Toussirot and Roudier, 2008; Cooke et al, 2008; Pordeus et al, 2008), Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (Lorusso et al, 2009), Autism, Irritable Bowel Syndrome (Boorom, 2007) and neurodegenerative diseases (Arai et al, 2006; Kamer et al, 2008). The model is suggesting that these infections have evolved to promote wounding and chronic inflammation in order to suppress the adaptive immune system. Furthermore, the model would predict that once the host’s immune system is compromised in this way, the individual is then susceptible to additional co-infections and cancer.

The question must then arise, why would biosystems evolve what appears to be a blind side in the immune system, such that injury switches off adaptive immunity? The logical answer might be that this compromise has evolved in order to avoid genuine ‘autoimmune’ reactions during wound clearance and remodelling.

Ageing is a further promoter of diseases in this domain, as a growing lack of systemic and locally derived IGF-1 leads to susceptibility to invaders and unresolved stresses (Martens et al, 2003; Kjaer et al, 2006). During normal wound healing, local IGF-1 is released to supplement systemic IGF-1 and generate sufficient AT2 to counteract the activities of AT1. Local IGF-1 is released from the extra-cellular matrix by macrophages (released by the activity of Matrix Metalloproteinases) and is also produced locally via stimulation by activated fibroblasts, monocytes (Todorovic et al, 2008) and T cells (Toulon et al, 2009). Notably, in the Toulon et al study, IGF-1 production could not be detected in T cells isolated from chronic wounds.

B. Disease State: Chronic Growth Response

Beyond lessons in the wound response, much more can be learnt from the behaviour of cancer, in particular, where extremes in growth response can be observed. There are, for instance, many hormone-dependent 'benign' forms of growth, including those that can later become hormone-independent, and malignant. The action of IGF-1 and acceleratory steroids, not only promote the growth of the tumour, but also appear to provide an alternative means of immune suppression (Castro Cabezas et al, 1998; Maruo et al, 2004; Muller and von Werder, 1992; Platet et al, 2004; Sengupta and Wasylyk, 2004; Turney et al, 2004; Giannitrapani et al, 2006). The transition to malignancy through AT1 expression and wound response is most likely marked by growth of the tumour beyond the limits of its environment. In addition, the model serves to explain the increased risk of a cancer becoming malignant, following tissue damage through surgery, chemotherapy or radiotherapy (Baum et al, 2005; Fowble et al, 2001; Kara et al, 2001; Everett et al, 2008; Demicheli et al, 2007). Baum et al, thus, proposes that breast cancer surgery can induce angiogenesis and proliferation of distant dormant micrometastases, especially in young patients with positive nodes.

In the category of chronic Growth Response is also Cushing’s syndrome, commonly associated as a side effect of steroid use, and notably, in some cases, caused by tumour-stimulated production of Adrenocorticotropin (Castro Cabezas et al, 1998; Muller and von Werder, 1992; Turney et al, 2004).

It would be also logical to expect many viral diseases to be found in this domain, and this is evident in the scientific literature (Brooke and Sapolsky, 2000; Congote, 2005; Iwakiri et al, 2005; Katagiri et al, 2006; Silverman et al, 2005; Sonnex, 1998; Tseng et al, 2005) of the induced Growth Response promoting viral replication and immune suppression. Lawson et al also propose that hormone responsive viruses such as Human papillomaviruses, mouse mammary tumour virus and Epstein-Barr virus may the prime candidate causes of breast cancer (Lawson et al, 2006). Many viruses offer an additional risk to carcinogenesis. All viruses (even those considered benign) have to hijack and promote host cell growth in order to replicate. Numerous mechanisms are employed, DNA and RNA sequences are inserted into the host, growth factors are stimulated and anti-growth factors are suppressed. Viral infections, thus, increase the risk of cell mutation and population growth, and for these reasons provide another target of interest for cancer prevention, with some well known examples shown in Table 2.

In addition to viral strategies that directly stimulate factors for immune suppression through the growth response, it is postulated that the chronic inflammation that arises from liberated viral toxins, particularly when their host cells are destroyed, is also an evolved mechanism to suppress the adaptive immune response (thereby protecting future generations of the virus). A review by Zúñiga MC (2003), ‘Lessons in Détente or know thy host: The immunomodulatory gene products of myxoma virus’, highlights that the virus has evolved to stimulate innate responses and apoptosis of surrounding host cells through the generation of a number of products such as TNF-alpha.

Table 2: The marked association between a number of specific cancers and viral infections is highlighted.

(http://info.cancerresearchuk.org/cancerstats/causes/infectiousagents/virusesandcancer/?a=5441#basicmech)

C. Disease State: Chronic Immune Response

Perhaps best described as diseases of hypersensitivity and allergy, conditions like Asthma, COPD and Allergic Rhinitis belong in this domain. These diseases often feature tissue that contains a preponderance of sensitised Esonophils, Mast cells and Basophils. Although at the extreme end of chronic immune responses, IL-4 plays undoubtedly an important role in sustaining disorders in this area. On reflection, the affected tissue could again be recognised as wounds that will not heal and that an exaggerated wound response has become manifest as a result of prolonged stress (Bullock et al, 2001). The relationship between asbestos and lung diseases likely falls into this category. Of particular note is that Angiotensin Converting Enzyme (ACE) levels have been reported to increase in line with increasing levels of inflammation in asbestos workers (Owczarek and Lewczuk, 1991).

The cause of these allergic diseases is currently explained as genetic susceptibility and environmental exposures. However, many invaders take advantage of the benefits of the environment and exacerbate the course of the disease (Tamari et al, 2009; Murphy, 2006; Sethi, 2006; Pelaia et al, 2006; Pinto Mendes, 2008; Tauro et al, 2008). It is thus possible that some invaders not only promote, but also actually cause this state in order to evade innate responses that might otherwise be effective. A review by Walton RP and Johnston SL, “Role of respiratory viral infections in the development of atopic conditions”, is one paper that supports this possibility (Walton and Johnston, 2008), with human rhinoviruses being shown to be the most prevalent cause of lower respiratory tract viral infections in infants, along with associated asthma development. Wu et al, also propose that a delay of exposure or prevention of winter viral infection during early infancy could prevent asthma (Wu et al, 2008). Respiratory Syncytial Virus has also been implicated as a cause of allergic type responses although the mechanism has yet to be defined (Belino-Studzinska and Pancer, 2008). Even the behaviour of HIV/AIDs has been compared to an allergic disease (Becker, 2004) due to raised levels of IgE and IL-4 in sera of HIV-1 infected and AIDS patients. Becker further proposes that a treatment that employs both antivirals and anti-allergen drugs may very well defeat the AIDS syndrome.

Blackburn and Wherry (2007) in their review, ‘IL-10, T cell exhaustion and viral persistence’ (Blackburn and Wherry, 2007), highlight the emerging role that IL10 has in the progression of viral diseases. They explain that viral infections can have one of two outcomes: control of viral replication and acute infection or viral persistence and chronic infection and that both pathogen and host characteristics influence the acute versus chronic outcome of viral infection. They highlight that blockade of IL-10R converted a chronic lymphocytic choriomeningitis virus infection into a rapidly controlled acute infection and prevented the functional exhaustion of memory T cells.

Also of interest is that ACE polymorphism has, in some studies, been found to play a role in the development of allergies too, with the DD phenotype being associated with more progressive and severe disease (Zhou et al, 2004; Urhan et al, 2004) and ACE polymorphism also being associated with aspirin intolerance in asthmatics (Kim et al, 2008). This intolerance might possibly be another bacterial toxin effect, given that staphylococcal superantigen-specific IgE antibodies have also been implicated in this area (Lee et al, 2006).

IX. Treating Diseases

In our current hypothesis, the response model is, of necessity, highly simplified. It provides, nevertheless, a conceptual framework for the consideration of disease treatment strategy. An understanding of the bigger picture regarding cellular responses, and the potential manipulation of these responses by invaders seems to provide an insight into potentially novel, effective, disease treatment strategies. Although the main focus in this paper is towards cancer and the use of agents that manipulate the Angiotensin system, the application and examination of supporting evidence is extended into other diseases.

A. Early clinical use of Angiotensin Receptor Blockers in treating cancers

1. Advanced Hormone Refractory Prostate Cancer, (Advanced HRPC)

The first clinical results published using Angiotensin Receptor Blockade in the treatment of cancer are made by Uemura et al (Uemura et al, 2005) in their pilot study in advanced hormone-refractory prostate cancer. Twenty-three patients who had already received secondary hormonal therapy using dexamethasone, and who were no longer receiving conventional therapy, were enrolled (patient characteristics shown in Table 3 below). Change in prostate-specific antigen (PSA), being an important marker of the disease, was determined as the primary endpoint. The secondary end-point was change in performance status (measured by the ability to perform daily tasks).

Table 3: Characteristics of the patients enrolled in the pilot study in advanced hormone-refractory prostate cancer

No of Patients Entered	23
Median age (range), years	75.9 (59-92)
Performance Status 0	12
Performance Status 1	8
Performance Status 2	3
Prior Hormone Treatment	23
Prior Radiotherapy	7
Prior Chemotherapy	5
Retropubic prostatectomy	1
Bone only metastasis	13
Soft Tissue only metastasis	2
Bone and Soft tissue metastasis	8

All of the patients received Candesartan 8 mg per day, being the maximum allowed dose for normal cardiovascular treatment in Japan, and androgen ablation (Orchiectomy or with blockade for luteinizing hormone-releasing hormone (LH-RH)). The Uemura group explained that they had not expected this low dose of an ARB (Angiotensin Receptor (Type 1) Blocker) to stop disease progression completely, especially in patients with advanced HRPC with widespread metastases, but they had hoped to delay it. Of the 23 patients enrolled in the current study, 1 patient did show an objective response on this low dose, with a 12.5% reduction in size of lung metastases. This patient had undergone total prostatectomy for well-differentiated adenocarcinoma. Unfortunately, PSA started to increase 2 years after the operation, and multiple lung metastases were found in July 1999. Although he had received Candesartan treatment since April 2001, his PSA increased continuously for 6 months after he started on the study. However, from November 2001, his bulky lung metastases showed shrinkage, associated with a decline in PSA from 267 to 177 ng/ml. He finally died of recurrence of lung metastases in May 2002, 36 months after the relapse of prostate cancer. With regard to the change in PS in the study, five patients showed an improvement in PS after starting Candesartan treatment. Although most patients had multiple metastases involving bone and lymph nodes, intriguingly, they did not require higher doses of opioid analgesics, or required only a minimal dose. PS was stable in another five patients with minimal use of analgesic agents (Uemura et al, 2005).

In summary, eight patients (34.8%) showed an effect on PSA levels; six showing a decrease immediately after starting administration and two showing a stable level of PSA. The six men with a PSA decline of more than 50% showed an improvement in performance status. The mean time to PSA progression across all responders was 8.3 months and one half of these patients showed stable or improved performance status during treatment. With regard to adverse effects, only one patient showed hypotension during treatment. Tissue analysis using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) staining showed that AT1 receptor expression in well-differentiated adenocarcinoma was higher than that in poorly differentiated adenocarcinoma (Uemura et al, 2005).

2. Treatment in Pheochromocytoma

More recently, Brown et al describes two patients with pheochromocytoma in whom treatment with higher dose angiotensin receptor blocker was associated with cessation of growth. Dosage of 300 mg Irbesartan (another AT1 blocker) per day was utilised in one patient and 16 mg Candesartan per day in the other (Brown et al, 2006).

Case 1

In 1984, a 32-year-old man presented with pheochromocytoma and the patient proceeded to surgical adrenalectomy with successful cure of his symptoms and hypertension. In 1997, he re-presented with hypertension, his plasma norepinephrine (a marker of progression) was elevated and did not suppress with pentolinium 2.5 mg. A CT scan showed a 1.5 cm mass in the right adrenal. No hot spots were found on 123ImIBG scan or selective venous sampling. The patient was therefore managed medically. Blood pressure was controlled by phenoxybenzamine, but there was a progressive increase in plasma norepinephrine to 3.3 ng/L. Additional therapy with an ARB, Irbesartan 150 mg, was started in 1999. In view of the rising plasma norepinephrine levels, the dose of Irbesartan was increased to 300 mg daily in 2001. Plasma norepinephrine peaked at 4 ng/mL and then appeared to decline in Figure .

Over 4 years from 1998 to 2002, the adrenal mass grew approximately 50% in diameter but from 2002, the size of tumour remained static, as judged by the results of the CT scans (shown in Figure 2).

Case 2

A 63-year-old man presented in 2000 with a large left adrenal phaeochromocytoma, confirmed with MRI scans and surgically removed. At follow-up over the next year, the patient remained well and normotensive, but in August 2004 the patient re-presented with a CT scan confirming local recurrence in the left adrenal bed and 18F-FDG scanning revealed both local and distal metastases. Surgical exploration revealed multiple peritoneal seedlings and no tumour was excised except for histological confirmation. Phenoxybenzamine was changed to doxazosin, which was better tolerated in this patient, and ARB therapy started with Candesartan 16 mg daily. Over the next year, plasma norepinephrine declined, Figure , and the mass of tumour in the adrenal bed appeared unchanged or slightly reduced through analysis of serial CT scans.

Both approaches appeared well tolerated with no adverse effects. The paper also highlights the observation that, in a patient with carcinoid syndrome and hypertension, introduction of Candesartan at 16–32 mg for his hypertension has been associated with an arrest of growth and 5HIAA excretion over a 3-year period. The purpose of their report was to encourage other physicians to consider high-dose ARB therapy, as a prelude to the design of a prospective, comparative trial.

3. Treatment in Advanced Renal Cancer

In three cases of metastatic renal cell carcinoma, Tatokoro et al (2008) found that a combination treatment of cimetidine (a Histamine Receptor II Antagonist), COX-2 inhibitor and RAS inhibitor (angiotensin converting enzyme inhibitor or angiotensin II type 1 receptor antagonist) (CCA therapy) was effective.

Case 1

Describes a 47-year-old man, CT scan revealing a 12-cm right renal mass invading the iliopsoas muscle with multiple pulmonary metastases, a large amount of pleural effusion and large hepatic metastases, providing a diagnosis of cT4N0M1 RCC. A combination therapy consisting of cimetidine 800 mg, etodolac, a selective COX-2 inhibitor, 10 mg and Candesartan 12 mg orally was provided. After he started CCA therapy, all the symptoms gradually disappeared and eight months later, the metastatic lesions reduced markedly in size, achieving a partial remission (> 50% reduction in tumour size) Figure 3. After a year, metastatic lesions enlarged again and he died another year later.

Figure 32: Results from Case 1. Computed tomography of the abdomen before (left) and eight months after (right) the start of CCA therapy.

Case 2

Describes a 62-year-old man presented with a metastatic left radial tumour from clear cell RCC. The patient, whose renal tumour was staged as T1bN0M1, underwent a left radical nephrectomy and resection of radial tumour followed by IFN-a subcutaneous for a year. The patient developed multiple pulmonary metastases eighteen months after the surgery and the metastatic lesions grew despite immune therapy (IFN-a and IL-2). When CCA therapy was started, all of the metastatic lesions gradually reduced in size and a nearly complete remission was achieved Figure . He has remained well without progression for 16 months.

Figure 13: Results from Case 2. Computed tomography of the chest before (left) and a year after (right) the start of CCA therapy.

Case 3

Describes a 64-year-old man presented with a 10-cm left renal tumour with multiple pulmonary metastases (pT3aN0M1). The patient underwent a left radical nephrectomy and IFN-a treatment commenced for six months until liver dysfunction. Since metastatic sites grew, CCA therapy of cimetidine 400 mg, meloxicam 10 mg and perindopril, ACE inhibitors, 4 mg orally was commenced. Metastatic lesions gradually reduced in size over two years, thus achieving a partial remission, Error! Reference source not found.. Brain metastases appeared 31 months later, however, and he died 41 months after the commencement of CCA therapy.

None of the three patients experienced any appreciable side effects associated with CCA therapy. Tatokoro et al (2008) report that is was highly unlikely that these tumour shrinkages in these cases were spontaneous regression of RCC. The reported incidence of spontaneous tumour regressions in RCC is extremely low (less than 1%), and most spontaneous regressions have been observed following the treatment of the primary tumours such as surgical removal, radiotherapy, or Embolisation.

Figure 14: Results from Case 3. Computed tomography of the chest before (left) and 14 months after (right) the start of combination treatment of CCA therapy.

4. Combination approaches in treating cancer and other invaders promoting wound response

Bacteria have also been shown to cause cancer to be more aggressive and patients with skin lymphoma could benefit from antibiotic treatments used for bacterial infections in lymphatic cancer (Woetmann et al, 2007). Ferreri et al (2006) have explored the association between ocular adnexal MALT lymphoma (OAL) and Chlamydia psittaci (Cp) infections (Ferreri et al, 2006), aiming to confirm reports suggesting that doxycycline treatment causes tumour regression in patients with Cp-related OAL. In this study, doxycycline proved a fast, safe, and active therapy for Cp DNA-positive OAL, effective even in patients with multiple failures, involving previously irradiated areas or regional lymphadenopathies.

Also of significant interest is that spontaneous tumour regression has been known to follow certain bacterial, fungal, viral, and protozoal infections. Dr. William Coley (1862–1936) was one of the first to capitalise on this characteristic and was reputed to have quite some success by injecting a cocktail of dead Streptococcus pyogenes and dead Serratia marcescens bacteria into tumours (Hoption Can et al, 2003). The approach, that still continues to date, leads to high fever and is associated with tumour regression. Advocates of the approach suggest tumour associated leucocytes display reparative functions that support tumour growth, but that intratumoural infections may reactivate defensive functions, causing tumour regression. The work by Tsung K, and Norton JA (2006), “Lessons from Coley's Toxin”, suggests that the effect is due to an increase in IL-12 (Tsung and Norton, 2006). Examination of the model would suggest that in these cases innate responses are being provoked. It would be a most interesting experiment to combine Angiotensin Receptor Blockade with Coley’s toxin to see if there is an enhanced effect. Similarly, although the literature is absent with regard to any attempt, the introduction of IL-2 in combination with AT1 blockers to treat not only cancer but also infections may prove to be beneficial.

Due to strong growth responses, it would seem likely that the application of agents that activate Retinoic Acid Receptors might be beneficial in cancer. Indeed a number of studies confirm this, especially when used in combination with other agents. Long-term results from children with high-risk neuroblastoma treated in a randomized trial with standard therapy followed by treatment with 13-cis-retinoic acid show that overall survival is significantly increased at the five-year point (Matthay et al, 2009). Clinical studies have also found combination therapies of interleukin-2 and 13-cis retinoic acids to be beneficial in the treatment of several cancers (Recchia et al, 2007; Recchia et al, 2005; Recchia et al, 2006; Recchia et al, 2008; Gilman et al, 2009), although dosage is important to optimise benefits Vs side effects. The additional effect of an Angiotensin Receptor Blocker to studies such as this might prove additionally synergistic.

Dobbs et al have hypothesised ongoing microbial insults as a progressive cause of idiopathic parkinsonism (Dobbs et al, 2008), their early studies have indeed shown that eradication of Helicobacter pylori infection has, on the whole, been proven beneficial to patients. Some patients, however, did react quite badly to treatment and had to be withdrawn from the study as a result of the toxic shock of the dying infections. In the case of the study by Dobbs et al (2008), it might be argued that these patients may well have been those with the greatest degree of infection (and the greatest need of infection eradication) and that a combination approach with AT1 blockade again might prove beneficial to avoid the side effects of an otherwise useful treatment. In fact, AT1 blockade has previously been demonstrated, in a number of animal studies, to ameliorate inflammation induced by endotoxins in a range of organs, including adrenal (Sanchez-Lemus et al, 2008), eye (Miyazaki et al, 2008) and lung (Zhang and Sun, 2006), as well as systemically (Laesser et al, 2004).

5. Approaches for the resolution of hypersensitivity

In this area, the diseases demonstrate an allergen-based chronic immune response as the cause; with also a resultant derived chronic injury response (wounding that does not heal). Potential means to treat such diseases might include either singly or in combination the use of the following approaches:

Ø IL-4 antagonists and ARBs might be beneficial, as they will relieve the chronic nature of the diseases as well as potentially stimulating improved innate responses.

Ø IL-10, IL-2 antagonists, IGF-1 and steroids might also appear beneficial and give short-term relief. However, the use of these agents will impair adaptive immune responses. If there is indeed an invader, such as a virus, promoting an allergic response, or other invaders taking advantage of the wound environment, then these may continue to propagate. It is proposed that the use of ARBs would be a suitable alternative to IGF-1 and steroids.

Yamagata and Ichinose in their review ‘Agents against cytokine synthesis or receptors’ (Yamagata and Ichinose, 2006), express disappointment that studies concerning the inhibition of interleukin (IL)-4 have been discontinued despite promising early results in asthma. They also suggest that ‘anti-inflammatory’ cytokines such as IL-10 may have a therapeutic potential. However, systemic delivery, as discussed earlier, may lead to longer-term deleterious effects.

Tarantini et al (2007), in their paper ‘Asthma treatment: magic bullets which seek their own targets' (Tarantini et al, 2007), provide an analysis of many of the different ways of interfering along the course of the cascade of the allergic reaction (including IL-4 and IL-10) and suggest that, at present, anti-IgE appear to be the only 'magic bullet' for the treatment of allergic asthma.

Regarding HIV, it has been reported that IL-10-secreting T cells from HIV-infected pregnant women down-regulate HIV-1 replication. An effect, which is enhanced by antiretroviral treatment (Bento et al, 2009).

6. Resolution of age related non-resolving wounds

Diseases in this category demonstrate a chronic immune response as the result of an inability to resolve wounding. Many of these diseases will likely progress with the aid of infections, however susceptibility increases due to aging as a result of the reduced availability of systemic and locally derived IGF-1. The use of both AT1 blockers and IGF-1 in diseases of ageing may promote repair, growth and healing. Once again, steroids will have a short-term benefit but will promote immune suppression.

In the ageing population, sarcopenia represents a progressive worsening of skeletal muscle mass and function, which is associated with declining growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. Preclinical studies have shown that infusion of angiotensin II produced a marked reduction in body weight, accompanied by decreased serum and muscle levels of IGF-1. In addition, IGF-1 serum levels have been shown to increase following ACE inhibitor treatment (Giovannini et al, 2008; Maggio et al, 2006). In the InCHIANTI study, in particular, of 745 subjects, it was found that treatment with ACE inhibitors for <3 years is associated with significantly higher levels of IGF-1. This association between the Angiotensin System and ageing has been considered for some time. This has been postulated to be associated with oxidative stress (Ferder et al, 2002) and specifically with changes in mitochondrial function (de Cavanagh et al, 2007).

X. Concluding Remarks

A great System Engineer was reputed to say "Everything should be made as simple as possible, but not simpler." http://en.wikiquote.org/wiki/Albert_Einstein The Cellular Response Model shown in

Figure lies at the very edge of this concept.

Cellular responses are indeed extremely complex and the biological system processes involve not only a great deal of redundancy but also synergistic behaviour in its components. Despite this and its simplicity the proposed model appears to be a powerful tool in considering disease management strategy and a means to explain the puzzle of inflammation and the perversion of healthy responses by cancer and infections.

A logical summary for the placement of the TH1 and TH2 model of diseases within the response model is also possible. Such that TH1 might be more appropriately viewed as an innate inflammatory response to a stimulus (driven by TLRs) to a pathogen that is resistant to this non-specific immune response. TH2 is an allergic response driven by sensitivity to an allergen, but again an ineffective one, with the adaptive immune system being effectively distracted. This model might also explain, in part, the mechanism by which the human foetus (which is considered "non-self") is protected from attack by the adaptive immune system.

As a final note, the prospects for Angiotensin Receptor Blockade, in particular for the treatment of wounds that will not heal, are profound and two clinical trials are currently in preparation by the authors to test the effects of established angiotensin receptor blockers in conjunction with standard chemotherapeutic and immunotherapeutic approaches to verify their efficacy in cancer.

XI. Competing interests

Gary R Smith is a founding director of Perses Biosystems Ltd. The Initial focus is to establish technical reputation through testing of the hypothesis by clinical trials purely in the interests of extending scientific understanding and without financial motivation. In the longer term, Perses’s ambition is to identify additional drug targets and agents to work in combination with AT1 blockers to treat a variety of diseases.

Sotiris Missailidis is a lecturer at the Department of Chemistry and Analytical Sciences of the Open University and is interested in understanding the molecular processes behind disease states for the potential development of more successful therapeutics in the future, and has no commercial interests in this work.

XII. Authors' contributions

Gary R Smith proposed the hypothesis through a holistic and objective approach backed by scientific literature review. Sotiris Missailidis has been the academic collaborator in the development of these ideas. Both authors have contributed to the authoring of this manuscript.

Acknowledgements

Gary R Smith would like to acknowledge family and friends, who have significantly contributed to this hypothesis through their experiences and questioning, notably Paul Jaep, a long term ME sufferer, Catherine O'Driscoll and especially Gary’s wife Alison. He would also like to make a special mention of his grandfather Thomas William Flowers to whom he would like to dedicate this paper.

Sotiris Missailidis would like to acknowledge the Open University for their financial support.

References

Abiko M, Rodgers KE, Campeau JD, Nakamura RM, Dizerega GS: Alterations of angiotensin II Receptor levels in sutured wounds in rat skin. J Invest Surg 1996, 9:447-453.

Altorki NK, Keresztes RS, Port JL, Libby DM, Korst RJ, Flieder DB, Ferrara CA, Yankelevitz DF, Subbaramaiah K, Pasmantier MW, Dannenberg AJ: Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 2003, 21:2645-2650.

Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB: Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 2008, 25:2097-2116.

Anders H-J, Banas B, Schlondorff D: Signaling Danger: Toll-Like Receptors and their Potential Roles in Kidney Disease. J Am Soc Nephrol 2004, 15:854-867.

Arafat HA, Gong Q, Chipitsyna G, Rizvi A, Saa CT, Yeo CJ: Antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor blockers in pancreatic ductal adenocarcinoma. J Am Coll Surg 2007, 204:996-1005; discussion 1005-1006.

Arai H, Furuya T, Mizuno Y, Mochizuki H: Inflammation and infection in Parkinson's disease. Histol Histopathol 2006, 21:673-678.

Arganaraz GA, Konno AC, Perosa SR, Santiago JF, Boim MA, Vidotti DB, Varella PP, Costa LG, Canzian M, Porcionatto MA, et al: The renin-angiotensin system is upregulated in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis. Epilepsia 2008, 49:1348-1357.

Arrieta O, Pineda-Olvera B, Guevara-Salazar P, Hernandez-Pedro N, Morales-Espinosa D, Ceron-Lizarraga TL, Gonzalez-De la Rosa CH, Rembao D, Segura-Pacheco B, Sotelo J: Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis. Br J Cancer 2008, 99:160-166.

Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP: Pleiotropic effects of statins--clinical evidence. Curr Pharm Des 2009, 15:479-489.

Attoub S, Gaben AM, Al-Salam S, Al Sultan MA, John A, Nicholls MG, Mester J, Petroianu G: Captopril as a potential inhibitor of lung tumor growth and metastasis. Ann N Y Acad Sci 2008, 1138:65-72.

Azad N, Rojanasakul Y, Vallyathan V: Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ Health B Crit Rev 2008, 11:1-15.

Baum M, Demicheli R, Hrushesky W, Retsky M: Does surgery unfavourably perturb the "natural history" of early breast cancer by accelerating the appearance of distant metastases? Eur J Cancer 2005, 41:508-515.

Becker Y: HIV-1 induced AIDS is an allergy and the allergen is the Shed gp120--a review, hypothesis, and implications. Virus Genes 2004, 28:319-331.

Bedair HS, Karthikeyan T, Quintero A, Li Y, Huard J: Angiotensin II receptor blockade administered after injury improves muscle regeneration and decreases fibrosis in normal skeletal muscle. Am J Sports Med 2008, 36:1548-1554.

Belino-Studzinska P, Pancer K: [Respiratory syncytial virus: as an etiological agent of respiratory tract infection in children and adults]. Przegl Epidemiol 2008, 62:767-775.

Ben-Haim S, Gacinovic S, Israel O: Cardiovascular infection and inflammation. Semin Nucl Med 2009, 39:103-114.

Bento CA, Hygino J, Andrade RM, Saramago CS, Silva RG, Silva AA, Linhares UC, Brindeiro R, Tanuri A, Rosenzwajg M, et al: IL-10-secreting T cells from HIV-infected pregnant women downregulate HIV-1 replication: effect enhanced by antiretroviral treatment. Aids 2009, 23:9-18.

Blackburn SD, Wherry EJ: IL-10, T cell exhaustion and viral persistence. Trends Microbiol 2007, 15:143-146.

Bondy B, Baghai TC, Zill P, Schule C, Eser D, Deiml T, Zwanzger P, Ella R, Rupprecht R: Genetic variants in the angiotensin I-converting-enzyme (ACE) and angiotensin II receptor (AT1) gene and clinical outcome in depression. Prog Neuropsychopharmacol Biol Psychiatry 2005, 29:1094-1099.

Boorom KF: Is this recently characterized gastrointestinal pathogen responsible for rising rates of inflammatory bowel disease (IBD) and IBD associated autism in Europe and the United States in the 1990s? Med Hypotheses 2007, 69:652-659.

Breslin JW, Wu MH, Guo M, Reynoso R, Yuan SY: Toll-like receptor 4 contributes to microvascular inflammation and barrier dysfunction in thermal injury. Shock 2008, 29:349-355.

Brody JS, Spira A: State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer. Proc Am Thorac Soc 2006, 3:535-537.

Brooke SM, Sapolsky RM: The effects of steroid hormones in HIV-related neurotoxicity: a mini review. Biological Psychiatry 2000, 48:881.

Brown ER, Charles KA, Hoare SA, Rye RL, Jodrell DI, Aird RE, Vora R, Prabhakar U, Nakada M, Corringham RE, et al: A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer. Ann Oncol 2008, 19:1340-1346.

Brown MJ, Mackenzie IS, Ashby MJ, Balan KK, Appleton DS: AT2 receptor stimulation may halt progression of pheochromocytoma. Ann N Y Acad Sci 2006, 1073:436-443.

Bullock GR, Steyaert I, Bilbe G, Carey RM, Kips J, De Paepe B, Pauwels R, Praet M, Siragy HM, de Gasparo M: Distribution of type-1 and type-2 angiotensin receptors in the normal human lung and in lungs from patients with chronic obstructive pulmonary disease. Histochem Cell Biol 2001, 115:117-124.

Busquets X, MacFarlane NG, Heine-Suner D, Morla M, Torres-Juan L, Iglesias A, Llado J, Sauleda J, Agusti AG: Angiotensin-converting-enzyme gene polymorphisms, smoking and chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2007, 2:329-334.

Cairns BA, Barnes CM, Mlot S, Meyer AA, Maile R: Toll-like receptor 2 and 4 ligation results in complex altered cytokine profiles early and late after burn injury. J Trauma 2008, 64:1069-1077; discussion 1077-1068.

Carey RM: Update on the role of the AT2 receptor. Curr Opin Nephrol Hypertens 2005, 14:67-71.

Castellon R, Hamdi HK: Demystifying the ACE polymorphism: from genetics to biology. Curr Pharm Des 2007, 13:1191-1198.

Castro Cabezas M, Vrinten DH, Burgers JA, Croughs RJM: Central diabetes insipidus and Cushing's syndrome due to ectopic ACTH production by disseminated small cell lung cancer: A case report. The Netherlands Journal of Medicine 1998, 53:32.

Chan AT, Ogino S, Fuchs CS: Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 2007, 356:2131-2142.

Chan YC, Leung PS: Involvement of Redox-Sensitive Extracellular-Regulated Kinases in Angiotensin II-Induced Interleukin-6 Expression in Pancreatic Acinar Cells. J Pharmacol Exp Ther 2009, 329: 450-458.

Chen FP, Gong LK, Zhang L, Wang H, Qi XM, Wu XF, Xiao Y, Cai Y, Liu LL, Li XH, Ren J: Early lung injury contributes to lung fibrosis via AT1 receptor in rats. Acta Pharmacol Sin 2007, 28:227-237.

Cheskis BJ, Greger JG, Nagpal S, Freedman LP: Signaling by estrogens. J Cell Physiol 2007, 213:610-617.

Chetty A, Nielsen HC: Regulation of Cell Proliferation by Insulin-like Growth Factor 1 in Hyperoxia-Exposed Neonatal Rat Lung. Molecular Genetics and Metabolism 2002, 75:265.

Chytil F: Retinoids in lung development. FASEB J 1996, 10:986-992.

Congote LF: Monitoring insulin-like growth factors in HIV infection and AIDS. Clin Chim Acta 2005, 361:30-53.

Cooke A, Ferraccioli GF, Herrmann M, Romani L, Schulze C, Zampieri S, Doria A: Induction and protection of autoimmune rheumatic diseases. The role of infections. Clin Exp Rheumatol 2008, 26:S1-7.

Cuatrecasas P: Drug discovery in jeopardy. J Clin Invest 2006, 116:2837-2842.

Dalgleish AG, O'Byrne K: Inflammation and cancer: the role of the immune response and angiogenesis. Cancer Treat Res 2006, 130:1-38.

D'Arpa N, Accardo-Palumbo A, Amato G, D'Amelio L, Pileri D, Cataldo V, Mogavero R, Lombardo C, Napoli B, Conte F: Circulating dendritic cells following burn. Burns 2009, 35:513-518.

de Cavanagh EM, Piotrkowski B, Fraga CG: The interaction between the renin-angiotensin system and peroxisome proliferator activated receptors: a hypothesis including the participation of mitochondria in aging. Front Biosci 2007, 12:1049-1062.

Deans DA, Tan BH, Wigmore SJ, Ross JA, de Beaux AC, Paterson-Brown S, Fearon KC: The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal cancer. Br J Cancer 2009, 100:63-69.

Debernardi-Venon W, Martini S, Biasi F, Vizio B, Termine A, Poli G, Brunello F, Alessandria C, Bonardi R, Saracco G, et al: AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol 2007, 46:1026-1033.

Delli Gatti C, Osto E, Kouroedov A, Eto M, Shaw S, Volpe M, Luscher TF, Cosentino F: Pulsatile stretch induces release of angiotensin II and oxidative stress in human endothelial cells: effects of ACE inhibition and AT1 receptor antagonism. Clin Exp Hypertens 2008, 30:616-627.

Demicheli R, Retsky MW, Hrushesky WJ, Baum M: Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures. Nat Clin Pract Oncol 2007, 4:699-710.

Dobbs RJ, Dobbs SM, Weller C, Charlett A, Bjarnason IT, Curry A, Ellis DS, Ibrahim MA, McCrossan MV, O'Donohue J, et al: Helicobacter hypothesis for idiopathic parkinsonism: before and beyond. Helicobacter 2008, 13:309-322.

Dolle L, Depypere HT, Bracke ME: Anti-invasive/anti-metastasis strategies: new roads, new tools and new hopes. Curr Cancer Drug Targets 2006, 6:729-751.

Drakopanagiotakis F, Xifteri A, Polychronopoulos V, Bouros D: Apoptosis in lung injury and fibrosis. Eur Respir J 2008, 32:1631-1638.

Dupont J, Pierre A, Froment P, Moreau C: The insulin-like growth factor axis in cell cycle progression. Horm Metab Res 2003, 35:740-750.

Erlinger TP, Muntner P, Helzlsouer KJ: WBC Count and the Risk of Cancer Mortality in a National Sample of U.S. Adults: Results from the Second National Health and Nutrition Examination Survey Mortality Study. Cancer Epidemiol Biomarkers Prev 2004, 13:1052-1056.

Esteban V, Gallego-Delgado J, Lazaro A, Osende J, Mezzano S, Egido J, Ruiz-Ortega M: Long-term treatment with an ACE inhibitor or an AT1 antagonist avoids hypertension-induced inflammation in the kidney. J Nephrol 2006, 19:725-731.

Everett M, Gutman H: Surgical management of gastrointestinal stromal tumors: analysis of outcome with respect to surgical margins and technique. J Surg Oncol 2008, 98:588-593.

Ferder LF, Inserra F, Basso N: Advances in our understanding of aging: role of the renin-angiotensin system. Curr Opin Pharmacol 2002, 2:189-194.

Ferrari V, Valcamonico F, Amoroso V, Simoncini E, Vassalli L, Marpicati P, Rangoni G, Grisanti S, Tiberio GA, Nodari F, et al: Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol 2006, 57:185-190.

Ferreri AJ, Ponzoni M, Guidoboni M, Resti AG, Politi LS, Cortelazzo S, Demeter J, Zallio F, Palmas A, Muti G, et al: Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst 2006, 98:1375-1382.

Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ: Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer. Br J Cancer 2004, 90:1704-1706.

Fowble B, Hanlon A, Freedman G, Nicolaou N, Anderson P: Second cancers after conservative surgery and radiation for stages I-II breast cancer: identifying a subset of women at increased risk. International Journal of Radiation Oncology*Biology*Physics 2001, 51:679.

Franscini LM, Von Vigier RO, Pfister R, Casaulta-Aebischer C, Fossali E, Bianchetti MG: Effectiveness and safety of the angiotensin II antagonist irbesartan in children with chronic kidney diseases. Am J Hypertens 2002, 15:1057-1063.

Gao J, Lin Y, Xiao Y, Xu K, Xu W, Zhu Y, Ma Y, Bai Y: Polymorphism of angiotensin-converting enzyme gene and genetic susceptibility to asthma with familial aggregation. Chin Med Sci J 2000, 15:24-28.

Garay RP, Viens P, Bauer J, Normier G, Bardou M, Jeannin JF, Chiavaroli C: Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur J Pharmacol 2007, 563:1-17.

Gard PR: Angiotensin as a target for the treatment of Alzheimer's disease, anxiety and depression. Expert Opin Ther Targets 2004, 8:7-14.

Ge J, Barnes NM: Alterations in angiotensin AT1 and AT2 receptor subtype levels in brain regions from patients with neurodegenerative disorders. Eur J Pharmacol 1996, 297:299-306.

Giannitrapani L, Soresi M, La Spada E, Cervello M, D'Alessandro N, Montalto G: Sex hormones and risk of liver tumor. Ann N Y Acad Sci 2006, 1089:228-236.

Gilliver SC, Ashcroft GS: Sex steroids and cutaneous wound healing: the contrasting influences of estrogens and androgens. Climacteric 2007, 10:276-288.

Gilliver SC, Ruckshanthi JP, Hardman MJ, Nakayama T, Ashcroft GS: Sex dimorphism in wound healing: the roles of sex steroids and macrophage migration inhibitory factor. Endocrinology 2008, 149:5747-5757.

Gilliver SC, Ruckshanthi JP, Hardman MJ, Zeef LA, Ashcroft GS: 5alpha-dihydrotestosterone (DHT) retards wound closure by inhibiting re-epithelialization. J Pathol 2009, 217:73-82.

Gilman AL, Ozkaynak MF, Matthay KK, Krailo M, Yu AL, Gan J, Sternberg A, Hank JA, Seeger R, Reaman GH, Sondel PM: Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group. J Clin Oncol 2009, 27:85-91.

Giovannini S, Marzetti E, Borst SE, Leeuwenburgh C: Modulation of GH/IGF-1 axis: potential strategies to counteract sarcopenia in older adults. Mech Ageing Dev 2008, 129:593-601.

Giustina A, Mazziotti G, Canalis E: Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 2008, 29:535-559.

Gnanalingham MG, Mostyn A, Dandrea J, Yakubu DP, Symonds ME, Stephenson T: Ontogeny and nutritional programming of uncoupling protein-2 and glucocorticoid receptor mRNA in the ovine lung. J Physiol (Lond) 2005, 565:159-169.

Goldman-Johnson DR, de Kretser DM, Morrison JR: Evidence that androgens regulate early developmental events, prior to sexual differentiation. Endocrinology 2008, 149:5-14.

Grammatopoulos TN, Jones SM, Ahmadi FA, Hoover BR, Snell LD, Skoch J, Jhaveri VV, Poczobutt AM, Weyhenmeyer JA, Zawada WM: Angiotensin type 1 receptor antagonist losartan, reduces MPTP-induced degeneration of dopaminergic neurons in substantia nigra. Mol Neurodegener 2007, 2:1.

Granucci F, Zanoni I, Feau S, Ricciardi-Castagnoli P: Dendritic cell regulation of immune responses: a new role for interleukin 2 at the intersection of innate and adaptive immunity. Embo J 2003, 22:2546-2551.

Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, Myers L, Klein EC, Liu G, Calvi C, et al: Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006, 312:117-121.

Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100:57-70.

Harrison ML, Obermueller E, Maisey NR, Hoare S, Edmonds K, Li NF, Chao D, Hall K, Lee C, Timotheadou E, et al: Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. J Clin Oncol 2007, 25:4542-4549.

Health News: The continuing genius of statins. These wonder drugs appear to prevent heart attack, stroke, and Alzheimer's, as well as lung function decline. Health News 2008, 14:3-4.

Heymes C, Levy BI: [Functions of AT2 receptors of angiotensin II]. Therapie 1998, 53:213-216.

Hitomi H, Fukui T, Moriwaki K, Matsubara K, Sun GP, Rahman M, Nishiyama A, Kiyomoto H, Kimura S, Ohmori K, et al: Synergistic effect of mechanical stretch and angiotensin II on superoxide production via NADPH oxidase in vascular smooth muscle cells. J Hypertens 2006, 24:1089-1095.

Hoption Cann SA, van Netten JP, van Netten C: Dr William Coley and tumour regression: a place in history or in the future. Postgrad Med J 2003, 79:672-680.

Hosseini-Khalili AR, Thompson J, Kehoe A, Hopkinson NS, Khoshbaten A, Soroush MR, Humphries SE, Montgomery H, Ghanei M: Angiotensin-converting enzyme genotype and late respiratory complications of mustard gas exposure. BMC Pulm Med 2008, 8:15.

Hoyer KK, Dooms H, Barron L, Abbas AK: Interleukin-2 in the development and control of inflammatory disease. Immunol Rev 2008, 226:19-28.

Hu C, Dandapat A, Sun L, Marwali MR, Inoue N, Sugawara F, Inoue K, Kawase Y, Jishage K, Suzuki H, et al: Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion. Hypertension 2008, 52:556-562.

Hunyady L, Catt KJ: Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol 2006, 20:953-970.

Ibragimov AI, McNeal CJ, Ritter LR, Walton JR: A mathematical model of atherogenesis as an inflammatory response. Math Med Biol 2005, 22:305-333.

Ikura Y, Ohsawa M, Shirai N, Sugama Y, Fukushima H, Suekane T, Hirayama M, Ehara S, Naruko T, Ueda M: Expression of angiotensin II type 1 receptor in human cirrhotic livers: Its relation to fibrosis and portal hypertension. Hepatol Res 2005, 32:107-116.

Imai N, Hashimoto T, Kihara M, Yoshida S, Kawana I, Yazawa T, Kitamura H, Umemura S: Roles for host and tumor angiotensin II type 1 receptor in tumor growth and tumor-associated angiogenesis. Lab Invest 2007, 87:189-198.

Ingber DE: Can cancer be reversed by engineering the tumor microenvironment? Semin Cancer Biol 2008, 18:356-364.

Ino K, Shibata K, Kajiyama H, Yamamoto E, Nagasaka T, Nawa A, Nomura S, Kikkawa F: Angiotensin II type 1 receptor expression in ovarian cancer and its correlation with tumour angiogenesis and patient survival. Br J Cancer 2006, 94:552-560.

Irani RA, Xia Y: The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008, 29:763-771.

Iwakiri D, Sheen TS, Chen JY, Huang DP, Takada K: Epstein-Barr virus-encoded small RNA induces insulin-like growth factor 1 and supports growth of nasopharyngeal carcinoma-derived cell lines. Oncogene 2005, 24:1767-1773.

Iwakura Y, Nakae S, Saijo S, Ishigame H: The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 2008, 226:57-79.

Iwata K, Sohda T, Irie M, Takeyama Y, Anan A, Shakado S, Sakisaka S: Angiotensin II type 1 receptor antagonist improves the prognosis in rats displaying liver cirrhosis induced by a choline-deficient diet. J Gastrointestin Liver Dis 2008, 17:21-25.

Jacobs EJ, Thun MJ, Bain EB, Rodriguez C, Henley SJ, Calle EE: A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. J Natl Cancer Inst 2007, 99:608-615.

Janes KA, Albeck JG, Gaudet S, Sorger PK, Lauffenburger DA, Yaffe MB: A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science 2005, 310:1646-1653.

Janiak P, Bidouard JP, Cadrouvele C, Poirier B, Gouraud L, Grataloup Y, Pierre F, Bruneval P, O'Connor SE, Herbert JM: Long-term blockade of angiotensin AT1 receptors increases survival of obese Zucker rats. Eur J Pharmacol 2006, 534:271-279.

Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, et al: Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 2005, 11:1173-1179.

Joglar B, Rodriguez-Pallares J, Rodriguez-Perez AI, Rey P, Guerra MJ, Labandeira-Garcia JL: The inflammatory response in the MPTP model of Parkinson's disease is mediated by brain angiotensin: relevance to progression of the disease. J Neurochem 2009, 109:656-669.

Johns Hopkins Med Lett Statins: true wonder drugs? Health After 50 2002, 14:1-2, 7.

Joseph D'Ercole A, Ye P: Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 2008, 149:5958-5962.

Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ: Inflammation and Alzheimer's disease: possible role of periodontal diseases. Alzheimers Dement 2008, 4:242-250.

Kara M, Alver G, Dizbay Sak S, Kavukcu S: Implantation metastasis caused by fine needle aspiration biopsy following curative resection of stage IB non-small cell lung cancer. European Journal of Cardio-Thoracic Surgery 2001, 20:868.

Katagiri D, Hayashi H, Victoriano AF, Okamoto T, Onozaki K: Estrogen stimulates transcription of human immunodeficiency virus type 1 (HIV-1). Int Immunopharmacol 2006, 6:170-181.

Kaufman RP: Dealing with a shifting paradigm. Physician Exec 1987, 13:10-14.

Kawajiri M, Mogi M, Osoegawa M, Matsuoka T, Tsukuda K, Kohara K, Horiuchi M, Miki T, Kira JI: Reduction of angiotensin II in the cerebrospinal fluid of patients with multiple sclerosis. Mult Scler 2008, 14:557-560.

Kehoe AD, Nikiforov AM, Alexanin SS, Neronov EG, Tikhomirova OV, Shun'kov VB, Makarova NV, Rabinovich E, Usmanova NM, Kazakov VI, et al: Angiotensin-converting enzyme genotype and encephalopathy in Chernobyl cleanup workers. Eur J Neurol 2009, 16:95-100.

Khor LY, Bae K, Pollack A, Hammond ME, Grignon DJ, Venkatesan VM, Rosenthal SA, Ritter MA, Sandler HM, Hanks GE, et al: COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial. Lancet Oncol 2007, 8:912-920.

Kikkawa F, Mizuno M, Shibata K, Kajiyama H, Morita T, Ino K, Nomura S, Mizutani S: Activation of invasiveness of cervical carcinoma cells by angiotensin II. Am J Obstet Gynecol 2004, 190:1258-1263.

Kim TH, Chang HS, Park SM, Nam BY, Park JS, Rhim T, Park HS, Kim MK, Choi IS, Cho SH, et al: Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmatics. Clin Exp Allergy 2008, 38: 1727: 1737.

Kitayama H, Maeshima Y, Takazawa Y, Yamamoto Y, Wu Y, Ichinose K, Hirokoshi K, Sugiyama H, Yamasaki Y, Makino H: Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries. Am J Hypertens 2006, 19:718-727.

Kjaer M, Magnusson P, Krogsgaard M, Moller JB, Olesen J, Heinemeier K, Hansen M, Haraldsson B, Koskinen S, Esmarck B, Langberg H: Extracellular matrix adaptation of tendon and skeletal muscle to exercise. J Anat 2006, 208:445-450.

Kluwe J, Mencin A, Schwabe RF: Toll-like receptors, wound healing, and carcinogenesis. J Mol Med 2009, 87:125-138.

Kobayashi T, Teruya M, Kishiki T, Endo D, Takenaka Y, Tanaka H, Miki K, Kobayashi K, Morita K: Inflammation-based prognostic score, prior to neoadjuvant chemoradiotherapy, predicts postoperative outcome in patients with esophageal squamous cell carcinoma. Surgery 2008, 144:729-735.

Krick S, Hanze J, Eul B, Savai R, Seay U, Grimminger F, Lohmeyer J, Klepetko W, Seeger W, Rose F: Hypoxia-driven proliferation of human pulmonary artery fibroblasts: cross-talk between HIF-1alpha and an autocrine angiotensin system. Faseb J 2005, 19:857-859.

Krutzik SR, Modlin RL: The role of Toll-like receptors in combating mycobacteria. Seminars in Immunology 2004, 16:35.

Kuhn DM, Ghannoum MA: Indoor Mold, Toxigenic Fungi, and Stachybotrys chartarum: Infectious Disease Perspective. Clin Microbiol Rev 2003, 16:144-172.

Kundu JK, Surh YJ: Inflammation: gearing the journey to cancer. Mutat Res 2008, 659:15-30.

Laesser M, Oi Y, Ewert S, Fandriks L, Aneman A: The angiotensin II receptor blocker candesartan improves survival and mesenteric perfusion in an acute porcine endotoxin model. Acta Anaesthesiol Scand 2004, 48:198-204.

Lalani AS, Barrett JW, McFadden G: Modulating chemokines: more lessons from viruses. Immunology Today 2000, 21:100.

Laudanno OM, Cesolari JA: [Angiotensin II AT1 receptor antagonists as antiinflammatory and gastric protection drugs]. Acta Gastroenterol Latinoam 2006, 36:76-80.

Lawson JS, Gunzburg WH, Whitaker NJ: Viruses and human breast cancer. Future Microbiol 2006, 1:33-51.

Lee B, Vouthounis C, Stojadinovic O, Brem H, Im M, Tomic-Canic M: From an Enhanceosome to a Repressosome: Molecular Antagonism between Glucocorticoids and EGF Leads to Inhibition of Wound Healing. Journal of Molecular Biology, 345:1083.

Lee JM, Yanagawa J, Peebles KA, Sharma S, Mao JT, Dubinett SM: Inflammation in lung carcinogenesis: new targets for lung cancer chemoprevention and treatment. Crit Rev Oncol Hematol 2008, 66:208-217.

Lee JY, Kim HM, Ye YM, Bahn JW, Suh CH, Nahm D, Lee HR, Park HS: Role of staphylococcal superantigen-specific IgE antibodies in aspirin-intolerant asthma. Allergy Asthma Proc 2006, 27:341-346.

Lerner UH: Bone remodeling in post-menopausal osteoporosis. J Dent Res 2006, 85:584-595.

Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL: Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res 1999, 84:1043-1049.

Li JY, Avallet O, Berthelon MC, Langlois D, Saez JM: Effects of growth factors on cell proliferation and angiotensin II type 2 receptor number and mRNA in PC12W and R3T3 cells. Mol Cell Endocrinol 1998, 139:61-69.

Liao YD, Xu H, Han Q, Lei J, Zhang YY, Wang ZH: [Expression of angiotensin II type 1 receptor in cervical squamous cell carcinoma and its clinical significance]. Zhonghua Zhong Liu Za Zhi 2007, 29:360-364.

Lilenbaum R, Socinski MA, Altorki NK, Hart LL, Keresztes RS, Hariharan S, Morrison ME, Fayyad R, Bonomi P: Randomized phase II trial of docetaxel/irinotecan and gemcitabine/irinotecan with or without celecoxib in the second-line treatment of non-small-cell lung cancer. J Clin Oncol 2006, 24:4825-4832.

Lin JJ, Yueh KC, Chang DC, Lin SZ: Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease. J Neurol Sci 2002, 199:25-29.

Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G: Immunological aspects of chronic fatigue syndrome. Autoimmun Rev 2009, 8:287-291.

Lyons A, Kelly JL, Rodrick ML, Mannick JA, Lederer JA: Major injury induces increased production of interleukin-10 by cells of the immune system with a negative impact on resistance to infection. Ann Surg 1997, 226:450-458; discussion 458-460.

Maggio M, Ceda GP, Lauretani F, Pahor M, Bandinelli S, Najjar SS, Ling SM, Basaria S, Ruggiero C, Valenti G, Ferrucci L: Relation of angiotensin-converting enzyme inhibitor treatment to insulin-like growth factor-1 serum levels in subjects >65 years of age (the InCHIANTI study). Am J Cardiol 2006, 97:1525-1529.

Mahnke K, Johnson TS, Ring S, Enk AH: Tolerogenic dendritic cells and regulatory T cells: a two-way relationship. J Dermatol Sci 2007, 46:159-167.

Mann JR, Backlund MG, DuBois RN: Mechanisms of disease: Inflammatory mediators and cancer prevention. Nat Clin Pract Oncol 2005, 2:202-210.

Marastoni S, Ligresti G, Lorenzon E, Colombatti A, Mongiat M: Extracellular matrix: a matter of life and death. Connect Tissue Res 2008, 49:203-206.

Martens JW, Sieuwerts AM, Bolt-deVries J, Bosma PT, Swiggers SJ, Klijn JG, Foekens JA: Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression. Thromb Haemost 2003, 89:393-404.

Martin P, Parkhurst SM: Parallels between tissue repair and embryo morphogenesis. Development 2004, 131:3021-3034.

Maruo T, Ohara N, Wang J, Matsuo H: Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update 2004, 10:207-220.

Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, Gerbing RB, London WB, Villablanca JG: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 2009, 27:1007-1013.

Maul B, Krause W, Pankow K, Becker M, Gembardt F, Alenina N, Walther T, Bader M, Siems WE: Central angiotensin II controls alcohol consumption via its AT1 receptor. Faseb J 2005, 19:1474-1481.

Maung AA, Fujimi S, L. Miller M, MacConmara MP, Mannick JA, Lederer JA: Enhanced TLR4 reactivity following injury is mediated by increased p38 activation. J Leukoc Biol 2005:jlb.1204698.

Maus U, Andereya S, Schmidt H, Zombory G, Gravius S, Ohnsorge JA, Niedhart C: [Therapy effects of testosterone on the recovery of bone defects]. Z Orthop Unfall 2008, 146:59-63.

Meduri GU: Clinical review: A paradigm shift: the bidirectional effect of inflammation on bacterial growth. Clinical implications for patients with acute respiratory distress syndrome. Critical Care 2002, 6:24 - 29.

Menaker RJ, Jones NL: Fascination with bacteria-triggered cell death: the significance of Fas-mediated apoptosis during bacterial infection in vivo. Microbes and Infection 2003, 5:1149-1158.

Menke MN, Menke NB, Boardman CH, Diegelmann RF: Biologic therapeutics and molecular profiling to optimize wound healing. Gynecol Oncol 2008, 111:S87-91.

Miller AC, Rashid RM, Elamin EM: The "T" in trauma: the helper T-cell response and the role of immunomodulation in trauma and burn patients. J Trauma 2007, 63:1407-1417.

Miyajima A, Kosaka T, Asano T, Asano T, Seta K, Kawai T, Hayakawa M: Angiotensin II type I antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. Cancer Res 2002, 62:4176-4179.

Miyazaki A, Kitaichi N, Ohgami K, Iwata D, Jin XH, Iwabuchi K, Morohashi T, Ohno S, Onoe K: Anti-inflammatory effect of angiotensin type 1 receptor antagonist on endotoxin-induced uveitis in rats. Graefes Arch Clin Exp Ophthalmol 2008, 246:747-757.

Mizoue S, Iwai M, Ide A, Suzuki J, Horiuchi M, Shiraishi A, Ohashi Y: Role of angiotensin II receptor subtypes in conjunctival wound healing. Curr Eye Res 2006, 31:129-136.

Mocellin S, Marincola F, Riccardo Rossi C, Nitti D, Lise M: The multifaceted relationship between IL-10 and adaptive immunity: putting together the pieces of a puzzle. Cytokine & Growth Factor Reviews 2004, 15:61.

Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR: Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock 2006, 26:430-437.

Moskowitz DW, Johnson FE: The central role of angiotensin I-converting enzyme in vertebrate pathophysiology. Curr Top Med Chem 2004, 4:1433-1454.

Muller OA, von Werder K: Ectopic production of ACTH and corticotropin-releasing hormone (CRH). The Journal of Steroid Biochemistry and Molecular Biology 1992, 43:403.

Munteanu I, Didilescu C: [Chemistry and toxicology of cigarette smoke in the lungs]. Pneumologia 2007, 56:41, 43-46.

Murphy E, Korach KS: Actions of estrogen and estrogen receptors in nonclassical target tissues. Ernst Schering Found Symp Proc 2006:13-24.

Murphy TF: The role of bacteria in airway inflammation in exacerbations of chronic obstructive pulmonary disease. Curr Opin Infect Dis 2006, 19:225-230.

Muthu K, He LK, Melstrom K, Szilagyi A, Gamelli RL, Shankar R: Perturbed bone marrow monocyte development following burn injury and sepsis promote hyporesponsive monocytes. J Burn Care Res 2008, 29:12-21.

Nagai N, Oike Y, Noda K, Urano T, Kubota Y, Ozawa Y, Shinoda H, Koto T, Shinoda K, Inoue M, et al: Suppression of ocular inflammation in endotoxin-induced uveitis by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci 2005, 46:2925-2931.

Nakamura H, Inoue T, Arakawa N, Shimizu Y, Yoshigae Y, Fujimori I, Shimakawa E, Toyoshi T, Yokoyama T: Pharmacological and pharmacokinetic study of olmesartan medoxomil in animal diabetic retinopathy models. Eur J Pharmacol 2005, 512:239-246.

Nakayama M, Inoguchi T, Sonta T, Maeda Y, Sasaki S, Sawada F, Tsubouchi H, Sonoda N, Kobayashi K, Sumimoto H, Nawata H: Increased expression of NAD(P)H oxidase in islets of animal models of Type 2 diabetes and its improvement by an AT1 receptor antagonist. Biochem Biophys Res Commun 2005, 332:927-933.

Neal CP, Mann CD, Sutton CD, Garcea G, Ong SL, Steward WP, Dennison AR, Berry DP: Evaluation of the prognostic value of systemic inflammation and socioeconomic deprivation in patients with resectable colorectal liver metastases. Eur J Cancer 2009, 45:56-64.

Nickenig G, Sachinidis A, Seewald S, Bohm M, Vetter H: Influence of oxidized low-density lipoprotein on vascular angiotensin II receptor expression. J Hypertens Suppl 1997, 15:S27-30.

Nicod LP, Pache JC, Howarth N: Fungal infections in transplant recipients. Eur Respir J 2001, 17:133-140.

Oakley F, Teoh V, Ching ASG, Bataller R, Colmenero J, Jonsson JR, Eliopoulos AG, Watson MR, Manas D, Mann DA: Angiotensin II activates IkappaB kinase phosphorylation of RelA at Ser536 to promote myofibroblast survival and liver fibrosis. Gastroenterology 2009 [Epub ahead of print].

Ogarkov OB, Sin'kov VV, Medvedeva TV, Gutnikova M, Nekipelov OM, Raevskaia L, Kuptsevich N, Kostiunin K, Skvortsova RG: [Polymorphism of genes of the renin-angiotensin system ACE, AT1R, and AT2R in patients with pulmonary tuberculosis]. Mol Gen Mikrobiol Virusol 2008:12-18.

Owczarek H, Lewczuk E: Serum peptide III-procollagen and ACE in asbestos workers. Pol J Occup Med Environ Health 1991, 4:127-133.

Ozacmak VH, Sayan H, Cetin A, Akyildiz-Igdem A: AT1 receptor blocker candesartan-induced attenuation of brain injury of rats subjected to chronic cerebral hypoperfusion. Neurochem Res 2007, 32:1314-1321.

Pasare C, Medzhitov R: Toll-like receptors: balancing host resistance with immune tolerance. Current Opinion in Immunology 2003, 15:677.

Pasare C, Medzhitov R: Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 2005, 560:11-18.

Paterson HM, Murphy TJ, Purcell EJ, Shelley O, Kriynovich SJ, Lien E, Mannick JA, Lederer JA: Injury primes the innate immune system for enhanced Toll-like receptor reactivity. J Immunol 2003, 171:1473-1483.

Peebles KA, Lee JM, Mao JT, Hazra S, Reckamp KL, Krysan K, Dohadwala M, Heinrich EL, Walser TC, Cui X, et al: Inflammation and lung carcinogenesis: applying findings in prevention and treatment. Expert Rev Anticancer Ther 2007, 7:1405-1421.

Peehl DM, Wong ST, Cramer SD, Gross C, Feldman D: Suramin, hydrocortisone, and retinoic acid modify inhibitory effects of 1,25-dihydroxyvitamin D3 on prostatic epithelial cells. Urologic Oncology: Seminars and Original Investigations 1995, 1:188.

Pelaia G, Vatrella A, Gallelli L, Renda T, Cazzola M, Maselli R, Marsico SA: Respiratory infections and asthma. Respir Med 2006, 100:775-784.

Pelletier G, Ren L: Localization of sex steroid receptors in human skin. Histol Histopathol 2004, 19:629-636.

Pinto Mendes J: The role of infection in asthma. Rev Port Pneumol 2008, 14:647-675.

Platet N, Cathiard AM, Gleizes M, Garcia M: Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Critical Reviews in Oncology/Hematology 2004, 51:55.

Pordeus V, Szyper-Kravitz M, Levy RA, Vaz NM, Shoenfeld Y: Infections and autoimmunity: a panorama. Clin Rev Allergy Immunol 2008, 34:283-299.

Rabbani MA, Mahmood MS, Mekan SF, Frossard PM: Association of angiotensin-converting enzyme gene dimorphisms with severity of lupus disease. Saudi J Kidney Dis Transpl 2008, 19:761-766.

Ramachandran V, Ismail P, Stanslas J, Shamsudin N, Moin S, Mohd Jas R: Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene with essential hypertension and type 2 diabetes mellitus in Malaysian subjects. J Renin Angiotensin Aldosterone Syst 2008, 9:208-214.

Recchia F, Saggio G, Cesta A, Alesse E, Gallo R, Necozione S, Rea S: Phase II randomized study of interleukin-2 with or without 13-cis retinoic acid as maintenance therapy in patients with advanced cancer responsive to chemotherapy. Anticancer Res 2005, 25:3149-3157.

Recchia F, Saggio G, Cesta A, Candeloro G, Di Blasio A, Amiconi G, Lombardo M, Nuzzo A, Lalli A, Alesse E, et al: Phase II study of interleukin-2 and 13-cis-retinoic acid as maintenance therapy in metastatic colorectal cancer. Cancer Immunol Immunother 2007, 56:699-708.

Recchia F, Saggio G, Nuzzo A, Biondi E, Di Blasio A, Cesta A, Candeloro G, Alesse E, Rea S: Multicenter phase 2 study of interleukin-2 and 13-cis retinoic acid as maintenance therapy in advanced non-small-cell lung cancer. J Immunother 2006, 29:87-94.

Recchia F, Sica G, Candeloro G, Necozione S, Bisegna R, Bratta M, Rea S: Maintenance immunotherapy in metastatic breast cancer. Oncol Rep 2008, 20:1173-1179.

Reckamp KL, Krysan K, Morrow JD, Milne GL, Newman RA, Tucker C, Elashoff RM, Dubinett SM, Figlin RA: A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Clin Cancer Res 2006, 12:3381-3388.

Reis e Sousa C: Activation of dendritic cells: translating innate into adaptive immunity. Current Opinion in Immunology 2004, 16:21.

Riaz AA, Wang Y, Schramm R, Sato T, Menger MD, Jeppsson B, Thorlacius H: Role of angiotensin II in ischemia/reperfusion-induced leukocyte-endothelium interactions in the colon. Faseb J 2004, 18:881-883.

Richmond RS, Tallant EA, Gallagher PE, Ferrario CM, Strawn WB: Angiotensin II stimulates arachidonic acid release from bone marrow stromal cells. J Renin Angiotensin Aldosterone Syst 2004, 5:176-182.

Rocken C, Neumann K, Carl-McGrath S, Lage H, Ebert MP, Dierkes J, Jacobi CA, Kalmuk S, Neuhaus P, Neumann U: The gene polymorphism of the angiotensin I-converting enzyme correlates with tumor size and patient survival in colorectal cancer patients. Neoplasia 2007, 9:716-722.

Rocken C, Rohl FW, Diebler E, Lendeckel U, Pross M, Carl-McGrath S, Ebert MP: The angiotensin II/angiotensin II receptor system correlates with nodal spread in intestinal type gastric cancer. Cancer Epidemiol Biomarkers Prev 2007, 16:1206-1212.

Rodriguez-Pallares J, Rey P, Parga JA, Munoz A, Guerra MJ, Labandeira-Garcia JL: Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS. Neurobiol Dis 2008, 31:58-73.

Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS: Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad Sci 2001, 947:271-292; discussion 292-273.

Ross R: Atherosclerosis--an inflammatory disease. N Engl J Med 1999, 340:115-126.

Saibeni S, Spina L, Virgilio T, Folcioni A, Borsi G, de Franchis R, Cugno M, Vecchi M: Angiotensin-converting enzyme insertion/deletion gene polymorphism in inflammatory bowel diseases. Eur J Gastroenterol Hepatol 2007, 19:976-981.

Sanchez-Lemus E, Murakami Y, Larrayoz-Roldan IM, Moughamian AJ, Pavel J, Nishioku T, Saavedra JM: Angiotensin II AT1 receptor blockade decreases lipopolysaccharide-induced inflammation in the rat adrenal gland. Endocrinology 2008, 149:5177-5188.

Savaskan E, Hock C, Olivieri G, Bruttel S, Rosenberg C, Hulette C, Muller-Spahn F: Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer's dementia. Neurobiol Aging 2001, 22:541-546.

Schneider CP, Schwacha MG, Chaudry IH: The role of interleukin-10 in the regulation of the systemic inflammatory response following trauma-hemorrhage. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2004, 1689:22.

Schulman IH, Raij L: The angiotensin II type 2 receptor: what is its clinical significance? Curr Hypertens Rep 2008, 10:188-193.

Schwacha MG, Daniel T: Up-regulation of cell surface Toll-like receptors on circulating gammadelta T-cells following burn injury. Cytokine 2008, 44:328-334.

Seckl JR, Meaney MJ: Glucocorticoid Programming. Ann NY Acad Sci 2004, 1032:63-84.

Sengupta S, Wasylyk B: Physiological and Pathological Consequences of the Interactions of the p53 Tumor Suppressor with the Glucocorticoid, Androgen, and Estrogen Receptors. Ann NY Acad Sci 2004, 1024:54-71.

Sethi S: Coinfection in exacerbations of COPD: a new frontier. Chest 2006, 129:223-224.

Shafiq N, Malhotra S, Pandhi P, Grover A: The "Statinth" wonder of the world: a panacea for all illnesses or a bubble about to burst. J Negat Results Biomed 2005, 4:3.

Shankar A, Wang JJ, Rochtchina E, Yu MC, Kefford R, Mitchell P: Association Between Circulating White Blood Cell Count and Cancer Mortality: A Population-Based Cohort Study. Arch Intern Med 2006, 166:188-194.

Sharma R, Hook J, Kumar M, Gabra H: Evaluation of an inflammation-based prognostic score in patients with advanced ovarian cancer. Eur J Cancer 2008, 44:251-256.

Sharma R, Zucknick M, London R, Kacevska M, Liddle C, Clarke SJ: Systemic inflammatory response predicts prognosis in patients with advanced-stage colorectal cancer. Clin Colorectal Cancer 2008, 7:331-337.

Shen L, Mo H, Cai L, Kong T, Zheng W, Ye J, Qi J, Xiao Z: LOSARTAN PREVENTS SEPSIS-INDUCED ACUTE LUNG INJURY AND DECREASES ACTIVATION OF NF-kappaB AND MAPKs. Shock 2009, 31: 500-506.

Shibata K, Kikkawa F, Mizokami Y, Kajiyama H, Ino K, Nomura S, Mizutani S: Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma. Tumour Biol 2005, 26:9-16.

Sica A, Allavena P, Mantovani A: Cancer related inflammation: the macrophage connection. Cancer Lett 2008, 267:204-215.

Silverman MN, Pearce BD, Biron CA, Miller AH: Immune Modulation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis during Viral Infection. Viral Immunology 2005, 18:41-78.

Slaviero KA, Clarke SJ, Rivory LP: Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol 2003, 4:224-232.

Smith CJ, Perfetti TA, King JA: Perspectives on pulmonary inflammation and lung cancer risk in cigarette smokers. Inhal Toxicol 2006, 18:667-677.

Smith GR, Missailidis S: Cancer, inflammation and the AT1 and AT2 receptors. J Inflamm (Lond) 2004, 1:3.

Smith GR: Treatment of Cancer in Conjunction with Other Agents. In Anticancer Therapeutics (Missailidis, ed); 2008: 349-364

Sonnex C: Influence of ovarian hormones on urogenital infection. Sex Transm Infect 1998, 74:11-19.

Sparks DL, Hunsaker JC, 3rd, Amouyel P, Malafosse A, Bellivier F, Leboyer M, Courtet P, Helbecque N: Angiotensin I-converting enzyme I/D polymorphism and suicidal behaviors. Am J Med Genet B Neuropsychiatr Genet 2009, 150B:290-294.

Steckelings UM, Henz BM, Wiehstutz S, Unger T, Artuc M: Differential expression of angiotensin receptors in human cutaneous wound healing. Br J Dermatol 2005, 153:887-893.

Steckelings UM, Wollschlager T, Peters J, Henz BM, Hermes B, Artuc M: Human skin: source of and target organ for angiotensin II. Exp Dermatol 2004, 13:148-154.

Sun G, Haginoya K, Dai H, Chiba Y, Uematsu M, Hino-Fukuyo N, Onuma A, Iinuma K, Tsuchiya S: Intramuscular renin-angiotensin system is activated in human muscular dystrophy. J Neurol Sci 2009, 280:40-48.

Sutmuller R, Garritsen A, Adema GJ: Regulatory T cells and toll-like receptors: regulating the regulators. Ann Rheum Dis 2007, 66 Suppl 3:iii91-95.

Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J: Inflammation and angiotensin II. Int J Biochem Cell Biol 2003, 35:881-900.

Tahir M, Sharma SK, Ashraf S, Mishra HK: Angiotensin converting enzyme genotype affects development and course of sarcoidosis in Asian Indians. Sarcoidosis Vasc Diffuse Lung Dis 2007, 24:106-112.

Tamari M, Harada M, Hirota T, Nakamura Y: Host molecular defense mechanisms against Chlamydophila pneumoniae and genetic studies of immune-response-related genes in asthma. Recent Pat Inflamm Allergy Drug Discov 2009, 3:17-25.

Tamura M, Chen YJ, Howard EF, Tanner M, Landon EJ, Myers PR: Lipopolysaccharides and cytokines downregulate the angiotensin II type 2 receptor in rat cardiac fibroblasts. Eur J Pharmacol 1999, 386:289-295.

Taranova AG, Maldonado D, 3rd, Vachon CM, Jacobsen EA, Abdala-Valencia H, McGarry MP, Ochkur SI, Protheroe CA, Doyle A, Grant CS, et al: Allergic pulmonary inflammation promotes the recruitment of circulating tumor cells to the lung. Cancer Res 2008, 68:8582-8589.

Tarantini F, Baiardini I, Passalacqua G, Braido F, Canonica GW: Asthma treatment: 'magic bullets which seek their own targets'. Allergy 2007, 62:605-610.

Tatokoro M, Fujii Y, Kawakami S, Fukui N, Komai Y, Saito K, Koga F, Morimoto S, Fukui I, Kihara K: Favorable response to combination treatment of cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin system inhibitor in metastatic renal cell carcinoma: Report of three cases. Int J Urol 2008, 15:848-850.

Tauro S, Su YC, Thomas S, Schwarze J, Matthaei KI, Townsend D, Simson L, Tripp RA, Mahalingam S: Molecular and cellular mechanisms in the viral exacerbation of asthma. Microbes Infect 2008, 10:1014-1023.

Toblli JE, Munoz MC, Cao G, Mella J, Pereyra L, Mastai R: ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats. Obesity (Silver Spring) 2008, 16:770-776.

Todorovic V, Pesko P, Micev M, Bjelovic M, Budec M, Micic M, Brasanac D, Ilic-Stojanovic O: Insulin-like growth factor-I in wound healing of rat skin. Regul Pept 2008, 150:7-13.

Toulon A, Breton L, Taylor KR, Tenenhaus M, Bhavsar D, Lanigan C, Rudolph R, Jameson J, Havran WL: A role for human skin-resident T cells in wound healing. J Exp Med 2009, 206: 743-750.

Toussirot E, Roudier J: Epstein-Barr virus in autoimmune diseases. Best Pract Res Clin Rheumatol 2008, 22:883-896.

Tsang SW, Cheng CH, Leung PS: The role of the pancreatic renin-angiotensin system in acinar digestive enzyme secretion and in acute pancreatitis. Regul Pept 2004a, 119:213-219.

Tsang SW, Ip SP, Leung PS: Prophylactic and therapeutic treatments with AT 1 and AT 2 receptor antagonists and their effects on changes in the severity of pancreatitis. Int J Biochem Cell Biol 2004b, 36:330-339.

Tseng RJ, Padgett DA, Dhabhar FS, Engler H, Sheridan JF: Stress-induced modulation of NK activity during influenza viral infection: role of glucocorticoids and opioids. Brain, Behavior, and Immunity 2005, 19:153.

Tsung K, Norton JA: Lessons from Coley's Toxin. Surg Oncol 2006, 15:25-28.

Turney MK, Nicholson WE, Kovacs WJ: Gene expression phenotyping of an ACTH-producing small cell lung cancer line. Molecular and Cellular Endocrinology 2004, 219:105.

U.S. Preventive Services Task Force recommendation statement. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer. Ann Intern Med 2007, 146:361-364.

Uemura H, Hasumi H, Kawahara T, Sugiura S, Miyoshi Y, Nakaigawa N, Teranishi J, Noguchi K, Ishiguro H, Kubota Y: Pilot study of angiotensin II receptor blocker in advanced hormone-refractory prostate cancer. Int J Clin Oncol 2005, 10:405-410.

Uppal SS, Haider MZ, Hayat SJ, Abraham M, Sukumaran J, Dhaunsi GS: Significant association of insertion/deletion polymorphism of the angiotensin-converting enzyme gene with rheumatoid arthritis. J Rheumatol 2007, 34:2395-2399.

Urhan M, Degirmenci I, Harmanci E, Gunes HV, Metintas M, Basaran A: High frequency of DD polymorphism of the angiotensin-converting enzyme gene in Turkish asthmatic patients. Allergy Asthma Proc 2004, 25:243-247.

Vairaktaris E, Yapijakis C, Tsigris C, Vassiliou S, Derka S, Nkenke E, Spyridonidou S, Vylliotis A, Vorris E, Ragos V, et al: Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with increased risk for oral cancer. Acta Oncol 2007, 46:1097-1102.

Vaziri ND, Bai Y, Ni Z, Quiroz Y, Pandian R, Rodriguez-Iturbe B: Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction. J Pharmacol Exp Ther 2007, 323:85-93.

Veillard NR, Mach F: Statins: the new aspirin? Cell Mol Life Sci 2002, 59:1771-1786.

Vigano A, Trutschnigg B, Kilgour RD, Hamel N, Hornby L, Lucar E, Foulkes W, Tremblay ML, Morais JA: Relationship Between Angiotensin-Converting Enzyme Gene Polymorphism and Body Composition, Functional Performance, and Blood Biomarkers in Advanced Cancer Patients. Clin Cancer Res 2009, 15: 2442-2447.

Vladutiu GD, Natelson BH: Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans. Muscle Nerve 2004, 30:38-43.

Organ/Disease	Mediators inhibited by AT1 blockade	Reference
Kidney disease	COX-2, 12-lipooxygenase, MCP-1, and PAI-1, activation of NFKβ, VEGF	Franscini et al, 2002; Vaziri et al, 2007; Esteban et al, 2006; Kitayama et al, 2006; Janiak et al, 2006
Pancreatitis	(Key markers of the disease, including IL-6	Tsang et al, 2004a; Tsang et al, 2004b; Chan and Leung, 2009
Type 2 diabetes	NAD(P)H oxidase and increased oxidative stress in islets of Type 2 diabetes	Nakayama et al, 2005
Liver fibrosis and cirrhosis	TNF-alpha, IL-6 and TGF-beta, NFKβ	Yoshiji et al, 2009; Oakley et al, 2009; Iwata et al, 2008; Debernardi-Venon et al, 2007; Ikura et al, 2005; Toblli et al, 2008
Skin	None noted in these studies.	Abiko et al, 1996; Steckelings et al, 2004
Eye, Uveitis, diabetic retinopathy	TNF-alpha, MCP-1 and ICAM-1.	Miyazaki et al, 2008; Nagai et al, 2005; Nakamura et al, 2005
Alzheimer’s, Huntington’s and Parkinson’s	None noted in these studies.	Ge and Barnes, 1996
Alzheimer’s,	None noted in these studies.	Ozacmak et al, 2007; Savaskan et al, 2001; Gard, 2004
Parkinson’s	NAPDH Oxidase, microglial activation	Joglar et al, 2009; Rodriguez-Pallares et al, 2008; Grammatopoulos et al, 2007
Mesial temporal sclerosis	None noted in this study.	Arganaraz et al, 2008
Muscle and Muscular dystrophy	TGF- β	Sun et al, 2009; Bedair et al, 2008;
Lung Diseases	TNF-alpha, IL-6, and IL-1beta	Shen et al, 2008; Chen et al, 2007; Bullock et al, 2001
Preeclampsia	None noted in these studies.	Irani and Xia, 2008; Xia et al, 2007
Adrenal Gland	LPS-induced aldosterone, COX-2 and IL-6	Sanchez-Lemus et al, 2008
Stomach (gastric ulcers)	‘antiinflammatory response’	Laudanno and Cesolari, 2006
Marfan syndrome	TGF-beta	Habshi et al, 2006
Alcoholism	Reduced alcohol intake	Maul et al, 2005
Bone, haematopoiesis	Arachidonic acid release and MCSF by bone marrow stromal cells	Richmond et al, 2004
Colitis	‘Protects against potent ischemia/reperfusion induced pro-inflammatory effects in the colonic microcirculation	Riaz et al, 2004

Summary

I. Background

II. Visualising Cancer – its two defining processes

III. Systems Thinking – Angiotensin, a new role in Cancer