Inflammation & Allergy - Drug Targets

(Formerly 'Current Drug Targets - Inflammation & Allergy')

ISSN: 1871-5281

Inflammation & Allergy - Drug Targets

Volume 6, Number 2, June 2007

Contents


CC-Chemokine Receptors in Chronic Obstructive Pulmonary Disease Pp. 75-79
Ken R. Bracke, Ingel K. Demedts, Guy F. Joos and Guy G. Brusselle
[Abstract]


Measuring T Cell Cytokines in Allergic Upper and Lower Airway Inflammation: Can We Move to the Clinic? Pp. 81-90
Dominique M.A. Bullens
[Abstract]


Heat Shock Paradox and a New Role of Heat Shock Proteins and their Receptors as Anti-Inflammation Targets Pp. 91-100
Yu Chen, Tracy S. Voegeli, Peter P. Liu, Earl G. Noble and R. William Currie
[Abstract]


MCP-1/CCL2 as a Therapeutic Target in Myocardial Infarction and Ischemic Cardiomyopathy Pp. 101-107
Ying Xia and Nikolaos G. Frangogiannis
[Abstract]


Genetics and Genomics of Hepatic Acute Phase Reactants: A Mini-Review Pp. 109-115
Andras K. Fulop
[Abstract]


Sublingual Specific Immunotherapy: State of the Art Pp. 117-126
Luis Garcia-Marcos, Jose M. Lucas Moreno and Jesus Garde Garde
[Abstract]


Neurogenic Inflammation and Asthma Pp. 127-132
Claire A. Butler and Liam G. Heaney
[Abstract]


Microvascular Theory of Exercise-Induced Bronchoconstriction in Asthma: Potential Implication of Vascular Endothelial Growth Factor Pp. 133-137
Hiroshi Kanazawa
[Abstract]


Systemic Inflammatory Response, Bacterial Translocation and Nitric Oxide Donors Pp. 139-141
Francisco S. Lozano Sánchez and R. Gonzalez-Sarmiento
[Abstract]




Abstracts


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CC-Chemokine Receptors in Chronic Obstructive Pulmonary Disease
Ken R. Bracke, Ingel K. Demedts, Guy F. Joos and Guy G. Brusselle

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and disability in the world, with a prevalence that is expected to increase in the next decades. The disease is characterized by a chronic inflammatory response of the airways and lungs to noxious particles and gases, mostly cigarette smoke. The molecular and cellular mechanisms that lead to this exaggerated influx of cells belonging to both the innate and adaptive immune system are not yet completely unravelled. However, there is now growing evidence that the recruitment of these inflammatory cells in response to cigarette smoke is largely regulated by chemokines acting as ligands for chemokine receptors. Several of these receptors, which fall mainly in the CC- or CXC-category, have been implicated in the pathogenesis of COPD. In this review we will focus mainly on the CC-family, as the involvement of CXC-receptors in COPD has already been extensively reviewed. In patients with COPD, several CC-chemokines like MIP-1α, MIP-3α, RANTES and MCP-1 are upregulated, suggesting the contribution of their respective receptor in the pathogenesis of the disease. Using knock out mice, this contribution has been further confirmed for CCR5 and CCR6, evidenced by an attenuated accumulation of inflammatory cells like macrophages, dendritic cells, neutrophils and CD8⁺ T-lymphocytes upon cigarette smoke-exposure. Moreover, mice deficient for CCR5 or CCR6 are partially protected from the development of pulmonary emphysema, another hallmark of COPD. These data suggest that chemokine receptors are potential therapeutic targets to reduce the chronic inflammation and parenchymal destruction in COPD.


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Measuring T Cell Cytokines in Allergic Upper and Lower Airway Inflammation: Can We Move to the Clinic?
Dominique M.A. Bullens

Recent insights regarding the development of allergic diseases such as allergic rhinitis, asthma and atopic eczema are based on the functional diversity of T helper (Th)1 and Th2 lymphocytes. Th2 cells (secreting Interleukin (IL)-4, IL-5, IL-9 and IL-13) are considered to be responsible for the induction and for many of the manifestations of atopic diseases. Local overproduction of Th2 cytokines at the site of allergic inflammation, and an intrinsic defect in the production of IFN-γ by Th1 cells in atopic individuals, have now been reported by several authors. Both IFN-γ and IL-10 have been suggested to play a modulatory role in the induction and maintenance of allergen-specific tolerance in healthy individuals. However, recent studies indicate that Th1 cells, secreting IFN-γ, might cause severe airway inflammation. On the other hand, ‘inflammatory T cells’ or Th17 cells, producing IL-17, could represent a link between T cell inflammation and granulocytic influx as observed in allergic airway inflammation.

We focus in this review on local (at the side of inflammation) T cell cytokine production and cytokine production by circulating T cells (after in vitro restimulation) from individuals with allergic airway disease, rhinitis and/or asthma. We furthermore review the changes in local T cell cytokine production and/or cytokine production by circulating T cells (after restimulation in vitro) from allergic/asthmatic individuals after treatment with anti-inflammatory agents or immunotherapy. Finally, we discuss whether measuring these T cell cytokines in the airways might be of diagnostic importance or could help to follow-up patients with allergy/asthma.


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Heat Shock Paradox and a New Role of Heat Shock Proteins and their Receptors as Anti-Inflammation Targets
Yu Chen, Tracy S. Voegeli, Peter P. Liu, Earl G. Noble and R. William Currie

This article discusses the role of heat shock proteins (Hsps) and their receptors as anti-inflammation targets. Hsps are highly conserved proteins that protect cells against noxious or deleterious stimulus. Intracellular Hsps function as molecular chaperones governing protein assembly, folding, or transport and as anti-apoptotic regulators of cell signalling pathways leading to cell death. In addition, intracellular Hsps have recently been shown to have an anti-inflammatory role in various inflammatory conditions such as infection, ischemia/reperfusion injury, and cardiovascular diseases. However, the heat shock response and the induction of Hsps have paradoxical effects against cell injury. Hsp induction before a pro-inflammatory stimulus is clearly beneficial but Hsp induction after a pro-inflammatory stimulus is cytotoxic. These paradoxical and contradictory effects may result from the different functions of intracellular versus extracellular Hsps. Extracellular Hsps released from cells with compromised integrity may function as danger signals activating innate immunity by interacting with their receptors. Therefore, modulating the levels of intracellular Hsps or the activities of Hsp receptors will be potential drug targets in inflammation.


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MCP-1/CCL2 as a Therapeutic Target in Myocardial Infarction and Ischemic Cardiomyopathy
Ying Xia and Nikolaos G. Frangogiannis

The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 mediates recruitment of mononuclear cells, modulates monocyte and lymphocyte phenotype and regulates fibrous tissue deposition and angiogenesis. MCP-1 is markedly induced in the infarcted myocardium and plays an important role in infarct healing and post-infarction remodeling. MCP-1 null mice exhibit decreased macrophage recruitment in the infarcted heart, delayed phagocytosis of dead cardiomyocytes, diminished fibroblast infiltration and attenuated left ventricular remodeling. Targeted deletion of CCR2, the primary MCP-1 receptor also protects from the development of adverse remodeling following myocardial infarction. In addition to its role in infarct healing, MCP-1 signaling plays an important role in the development of interstitial fibrosis in a mouse model of brief repetitive myocardial ischemia and reperfusion. Our review manuscript discusses the mechanisms responsible for MCP-1-mediated effects in the ischemic myocardium and explores MCP-1 targeting as a novel therapeutic approach in patients with myocardial infarction and ischemic non-infarctive cardiomyopathy.


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Genetics and Genomics of Hepatic Acute Phase Reactants: A Mini-Review
Andras K. Fulop

Systemic acute phase response is a component of innate immunity and a consequence of local or systemic inflammation. A prominent feature of acute phase reaction is the alteration of gene expression in hepatocytes. The classical acute phase reactants are released into the blood and may be exuded into other body fluids. Generally, they exert anti-inflammatory action and are important players of the homeostasis maintenance. The genetic background influences a person's response to disturbances of homeostasis, including infections, stress and tissue injury. The most frequent and physiologically relevant genetic polymorphisms of the representatives of classical acute phase proteins are discussed herein. The genetic variations of acute phase proteins or their regulators are associated with several pathological conditions. The high-throughput genomic and proteomic technologies combined with bioinformatics give the most recent approaches to the study and analysis of acute phase proteins, thereby widening the scope of the term ‘acute phase reactants’ or discovering novel ones. Simultaneous testing of numerous analytes, including acute phase proteins from the same, small volume sample may give diagnostic tools for diseases. Accumulating knowledge about acute phase reaction may lead to the development of novel therapies and other prevention alternatives.


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Sublingual Specific Immunotherapy: State of the Art
Luis Garcia-Marcos, Jose M. Lucas Moreno and Jesus Garde Garde

Sublingual immunotherapy (SLIT) was first attempted more than a century ago. After a long parenthesis probably related to the lack of impressive clinical results, the advances on allergen quantification and characterization, together with the improvements in the recombination techniques have renewed the interest in this therapy during the past decade. There are currently enough high quality clinical trials on its efficacy in the management of respiratory allergies (asthma and rhinoconjunctivitis) to conclude that SLIT could be an effective tool for the management of those diseases. This effectiveness has been shown both in children and in adults. However, while there are some clues related to the mechanism of action of SLIT, there is still much to know about it. In addition, more studies comparing the effectiveness of SLIT vs the standard subcutaneous immunotherapy (SCIT) are needed to definitely establish the role of SLIT in the treatment of allergic diseases. SLIT has proven a very safe therapy as compared to SCIT, a fact which adds a very important advantage to the sublingual route.


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Neurogenic Inflammation and Asthma
Claire A. Butler and Liam G. Heaney

Over the past number of decades there has been considerable interest in the role of neurogenic inflammation in asthma with the identification of many biologically active neuropeptides in the lung. Whilst there is convincing evidence of neurogenic inflammation in various animal models of asthma, the evidence in humans is less clear and replicating the experimental approaches in humans has proven difficult with different studies producing conflicting results. In terms of human studies, research has focused on whether pro-inflammatory neuropeptides are elevated in the asthmatic airway, and if so, what their functional effects are. There have also been studies to assess the efficacy of tachykinin receptor antagonists in improving indices of asthma control. Information to date would suggest that neuropeptides are present in human airways and are possibly upregulated in asthma, but this effect does not appear to be specific and may occur in other inflammatory airways conditions (chronic obstructive pulmonary disease (COPD) and smoking). At present there is insufficient evidence to suggest that tachykinin receptor antagonists confer any additional benefit over inhaled corticosteroid regimes for asthmatic patients.


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Microvascular Theory of Exercise-Induced Bronchoconstriction in Asthma: Potential Implication of Vascular Endothelial Growth Factor
Hiroshi Kanazawa

Exercise-induced bronchoconstriction (EIB) is used to describe the increase in airway resistance that follows exercise in asthmatic patients. To date, two major hypotheses, water- and heat-loss theory, have been put forward to explain the mechanism of EIB. However, there is increasing evidence that airway microcirculation has the potential to contribute to the pathophysiological mechanisms of EIB. Bronchial asthma is a chronic airway inflammatory disease associated with airway remodeling, including the growth and proliferation of new blood vessels. Airway microvascular remodeling is likely to be induced by several growth factors, such as vascular endothelial growth factor (VEGF). VEGF has powerful effects on vascular function and also increases microvascular permeability. In this respect, high expression of VEGF in asthmatic airways contributes to the pathogenesis of EIB via increased airway microvascular permeability. Moreover, endothelial cells in airway microcirculation stimulated by high levels of VEGF is sensitive to exercise challenge and therefore, the change in circulating thrombomodulin levels with exercise can be an index of functional properties in endothelial cells. In this review, we will demonstrate the possible roles of VEGF on EIB in asthmatic patients in details. I will then propose a molecular mechanism explaining the microvascular theory of EIB based on functional abnormalities of endothelial cells in newly generated microvessels in asthmatic airways. These findings suggest that the intervention against VEGF offers a possible new strategy for the treatment of EIB in asthmatic patients.


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Systemic Inflammatory Response, Bacterial Translocation and Nitric Oxide Donors
Francisco S. Lozano Sánchez and R. Gonzalez-Sarmiento

Abdominal aortic surgery is relatively common and is associated with considerable post-operative morbidity and death. The aortic cross-clamping (supra or infrarenal) necessary for the insertion of a vascular graft, often in circumstances of haemorrhagic shock (e.e. a ruptured aneurysm) elicits a Systemic Inflammatory Response Syndrome (SIRS) and an Ischaemia-Reperfusion syndrome (I-R), with affectation of many organs including the kidneys and the intestine.

Experimentally, the exogenous use of nitric oxide donors has proved to be able to control the SIRS, minimising the damage due to I-R and protecting from renal dysfunction and BT. However, clinical experience in these situations is still limited.

Here we review the current status and experience of the authors in the use of nitric oxide donors in the control of the SIRS induced by infrarenal, suprarenal aortic cross-clamping, with or without haemorrhagic shock; and the Bacterial Translocation phenomenon (BT) induced by aortic cross-clamping below the mesenteric artery with or without associated hemorrhaging.