Inflammation & Allergy-Drug Targets (Discontinued) - Volume 8, Issue 3, 2009

Bone turnover is much important in normal homeostasis of body skeleton. Medications, nutritional status, and systemic illnesses may affect bone metabolism by altering biochemical mediators. Prostaglandins, especially of E and F series are much important in bone physiology by affecting osteoclastic activity and osteoblastic differentiation. In bone fracture, production of prostaglandins affects fracture healing. There is the possibility that non-steroidal anti-inflammatory drugs (NSAIDs) affect bone health by inhibiting cyclooxygenase (COX) enzymes which reduce synthesis of prostaglandins. The aim of this paper is to review the effects of NSAIDs on bone by evaluating both animal and human studies. Using key words such as bone, bone marker, bone mineral density, NSAIDs, COX inhibitor, bone metabolism and search engines like Web of sciences, Scopus, Pubmed, and Google scholar, all relevant studies were collected. Although NSAIDs showed anti-resorptive properties in animal studies and some few human studies, to date no conclusive result has been observed in bone formation. Some limited studies reported higher bone mineral density in daily users of NSAIDs.

Bronchial airway microvasculature consists in a developed network of vessels, which plays an important role in normal homeostasis as well as in inflammatory airway processes. Its airway autonomic neural control includes cholinergic and adrenergic innervation, as well as nonadrenergic noncholinergic system. The nerve/vessel interplay is complex and not yet completely clarified. In response to inspired air conditions, the sensory nerves can recruit appropriate reflexes, which can induce different vascular processes, such as vasodilatation, vasoconstriction, plasma extravasation and exudation. Additionally, the stimulation of C fibres may result in an axon local reflex with antidromic conduction down afferent nerve collaterals and release of sensory neuropeptides, which in turn may act on the mucosal vasculature to promote vasodilatation and microvascular leakage. The neurogenic inflammation may play a key role in allergic diseases, such as asthma, as well as in COPD, a smoking-related disease. This review deals with the interactions of vessels and nerves within the airway mucosa under healthy conditions and in inflammatory diseases. The clinical and pharmacological implications are also described.

Platelet activating factor (PAF) is a phospholipid mediator of inflammation that is released early in inflammation by a variety of cell types. PAF acts largely by binding to its receptor, PAF-R, a G-protein coupled receptor found on a variety of cells, including cells of the immune system. PAF has been implicated in the pathogenesis of asthma and allergic conditions, but its role in autoimmune conditions has been less extensively investigated. Here, we review the accumulating evidence for the role of PAF/PAF-R pathway in autoimmune diseases. We describe studies showing up-regulation of PAF-R in inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis and review the evidence from the use of PAF-R antagonists. We describe results of experimental models of inflammatory diseases that point to a role for PAF/PAF-R pathway including those using PAF-R antagonists and those employing PAF-R knockout mice and knockout mice for cytosolic phospholipase2. Recent experiments from our laboratory show that PAF/PAF-R pathway may influence T cell responses and favour the Th17 phenotype (in which T cells produce tissue destructive proinflammatory cytokine IL-17). The PAF/PAF-R pathway is a promising target for pharmacological intervention in autoimmune diseases.

Toll like receptors (TLRs) have been extensively studied since their discovery in 1997, and an increasingly detailed picture is emerging about their role in health and disease. TLRs, the first identified family of pattern recognition receptors, can recognize invaders through the exogenous pathogen-associated molecular patterns (PAMPs) and tissue injury through the endogenous danger-associated molecular patterns (DAMPs). In addition to immunocytes, TLRs are widely distributed in various cell types, including renal cells where they are thought to play a significant role in immune activation to pathogens, as well as the development and course of various kidney pathologies. This review summarizes the present data about the important role TLRs play in kidney diseases focusing on the specific role of PAMPs versus DAMPs and of local versus systemic TLR activation.

Infection with respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection in infants. It is accompanied by a considerably disease burden and a hospitalisation rate of up to 3% in infected infants. Besides, it is still a matter of intensive discussion whether severe RSV infection in early infancy causes the development of asthma later in live or whether RSV bronchiolitis just chronologically precedes asthma in children who are susceptible to asthma. The latter could be due to a common genetic background of both diseases predisposing to an exaggerated inflammatory response of the lungs to allergens and pathogens. Genetic studies might help to elucidate the mechanisms leading to both diseases and to highlight common as well as diverse pathways. The results of such investigations will influence the current understanding of the diseases and might even change our therapeutical approaches to both disorders. This review summarizes current findings in the genetics of bronchial asthma and severe RSV bronchiolitis. The question whether a relationship exists between severe RSV bronchiolitis in infancy and childhood asthma will also be discussed by taking recent epidemiological studies in account. A special focus is laid on the implications of these findings for a targeted drug therapy of both diseases.

The cell adhesion molecule CD44 is expressed on the majority of immune cells and is responsible for mediating adhesion to the extracellular matrix glycosaminoglycan, hyaluronan. The binding of CD44 to hyaluronan is induced on T lymphocytes after activation by antigen and on monocytes after stimulation by inflammatory agents. Under inflammatory conditions, CD44 on endothelial cells presents hyaluronan to CD44 on activated T lymphocytes and mediates a rolling interaction under flow conditions. This rolling interaction together with chemokine signaling upregulates integrinmediated adhesion, which induces cell arrest and leads to subsequent migration to the inflammatory site. Studies with monoclonal antibodies against CD44 in mouse models of chronic inflammatory disease showed reduced disease severity attributed to reduced leukocyte recruitment. More recent investigations, taking advantage of the availability of CD44 null mice, further established a role for CD44 in leukocyte recruitment to inflammatory sites. These studies also revealed a role for CD44 in limiting the inflammatory response and resolving inflammation in models of lung injury and hepatitis. Here we describe the contributions of CD44 and hyaluronan to an inflammatory response and discuss the role of CD44 in both promoting and resolving inflammation in various mouse models of inflammatory disease.

T cells play central roles in regulation of the immune system in mammals. T cell receptor αβ T cells that can produce the cytokine IL-17 are called Th17 cells and form a lineage of effector T cells that are distinct from Th1, Th2 and FoxP3+ T cells. The primary function of Th17 cells is to fight infection by bacterial and fungal pathogens. Autoreactive Th17 cells are implicated in mediating inflammation in the central nerves system, joints and other tissues. Th17 cells express a number of chemokine receptors including a secondary lymphoid tissue homing receptor (CCR7), the B follicle homing receptor (CXCR5), and non-lymphoid tissue homing receptors (CCR4, CCR5, and CXCR6). While these receptors are heterogeneously expressed by Th17 cells and have the potential to guide the migration of Th17 cell subsets into various tissues, CCR6 is uniformly expressed by most Th17 cells regardless of their tissue tropism. CCR6 plays an important role in migration of Th17 cells to inflamed tissues. Another function of CCR6 is to localize Th17 cells close to CCL20 expressing cells in the intestine, which would be important for the homeostasis of Th17 cells. Thus, chemokine receptors appear to play complex roles in the biology of Th17 cells.

Flavonoids are polyphenolic compounds that occur ubiquitously in plants having a variety of biological effects both in vitro and in vivo. They have been found to have antimicrobial, antiviral, anti-ulcerogenic, cytotoxic, antineoplastic, mutagenic, antioxidant, antihepatotoxic, antihypertensive, hypolipidemic, antiplatelet and anti-inflammatory activities. Flavonoids also have biochemical effects, which inhibit a number of enzymes such as aldose reductase, xanthine oxidase, phosphodiesterase, Ca+2-ATPase, lipoxygenase, cycloxygenase, etc. They also have a regulatory role on different hormones like estrogens, androgens and thyroid hormone. They have been found to have anti-inflammatory activity in both proliferative and exudative phases of inflammation. Several mechanisms of action have been proposed to explain anti-inflammatory action of flavonoids. The aim of the present review is to give an overview of the mechanism of action of potential anti-inflammatory flavonoids.

C3a and C5a, the small (∼10KDa) cleavage fragments released by complement activation, are potent mediators of inflammation. They are anaphylatoxins and act as cell activators with nanomolar affinity, exerting their functions through binding to specific receptors (C3aR and C5aR or C5L2 respectively). Recent studies suggest that locally generated complement effector molecules including C3a and C5a contribute to pathological processes in inflammatory and immunological diseases as well as adaptive immune response besides its host defence mechanism. Targeting the receptors and/or their ligands can reduce undesired inflammatory responses and tissue damage in certain pathological conditions. In this article we describe the recent developments in this important area and focus on the role of C3a/C5a in inflammatory and autoimmune diseases and in adaptive immune responses.