Inflammatory processes

Glucocorticoids have been shown to inhibit gene transcription of other proteins involved in the inflammatory process, including the key inflammation mediators called cytokines (IL-1, IL3—6, IL8, GM-CSF, TNFa) (10,58,63—65). Steroids have been also shown to suppress the formation of cytokine receptors (10) dexamethasone, in particular, downregulates gene transcription of angiotensin II type 2 receptors (66). 

These steioids aie capable of preventing or suppressing the development of the sweUing, redness, local heat, and tenderness which characterize inflammation. They inhibit not only the acute symptoms of the inflammatory process, such as edema, fibrin deposition, and capillary dilatation, but also the chronic manifestations. There is evidence that glucocorticoids induce the synthesis of a protein that inhibits phosphoHpase A 2 (60), diminishing the release of arachidonic acid from phosphoHpids (Fig. 2), thereby reducing chemotaxis and inflammation. 

FIGURE 9.11 An example of a cellular system designed to study inflammatory processes related to asthma and arthritis. Multiple readouts (ELISA measurements) from each of four cell types are obtained under conditions of four contexts (mixture of stimulating agents). This results in a complex heat map of basal cellular activities that can be affected by compounds. The changes in the heat map (measured as ratios of basal to compound-altered activity) are analyzed statistically to yield associations and differences. 

Acute phase reactants (e.g., C-reactive protein) are proteins that increase during inflammation and are deposited in damaged tissues. They were first discovered in the serum, but are now known to be involved in inflammatory processes in the brain (e.g., found in the brain of Alzheimer patients and associated with amyloid plaques). 

One intensively investigated feature of the inflammatory process in COPD is the release of proteases from neutrophils and monocytic cells that destroy elastin and other components of the interstitial matrix (Table 1). The best studied protease is neutrophil elastase. Independent of its elastolytic activity, neutrophil elastase is a potent secretagogue. More recently matrix metalloproteases (MMP) have received increasing attention, in particular MMP 12 (macrophages elastase). To which extent and how exactly these proteases become activated is not clear at present. 

Parallel to orchestrating acute inflammatory processes by providing an optimal milieu of cytokines, mediators, and adhesion molecules in order to recruit and activate effector cells to the site of infection, dendritic cells also setve as professional antigen-presenting cells for cells of the adaptive immune system ( antigen presentation ... 

Many low weight compounds produced by microor-ganism-like formylated peptides as well as endogenous mediators are chemotactic for leukocytes and promote the inflammatory process. The main endogenous compounds are listed in Table 1 and are derived from activated plasma protein cascades that function as amplification mechanisms, are performed and released from activated cells or are de novo synthesized on demand by cells participating in or being affected by inflammatory events. The major modulators of leukocyte adhesion to endothelial cells are listed in Table 2. 

IFN- 3 reduces the induction by inflammatory cytokines of adhesion molecules and of MHC class I and II complex on endothelial cells, a process preceding attachment and transendothelial migration of T-cells. These anti-inflammatory effects of IFN- 3 exemplify antagonistic actions of type I and type IIIFN. There is, indeed, much clinical evidence for the involvement of IFN-y in inflammatory processes - through activation of iNOS and subsequent secretion of NO - leading to the establishment of autoimmune diseases as for instance in rheumatoid arthritis. 

Cytokines are small, short-lived proteins and important mediators of local intercellular communication. They play a key role in integrating responses to a variety of stimuli in immune and inflammatory processes. By binding their cognate receptors on target cells in their immediate vicinity, these molecules participate in many important biological activities including cell proliferation, activation, death and differentiation. In... 

Corticosteroids, such as beclomethasone (Beclovent), flu-nisolide (AeroBid), and triamcinolone (Azmacort), are given by inhalation and act to decrease the inflammatory process in the airways of the patient with asthma, hi addition, the corticosteroids increase the sensitivity of the p2-receptors. With increased sensitivity of the ( -receptors, the p2-receptor agonist drugs are more effective... 

Leuko trienes are bronchoconstrictive substances released by the body during the inflammatory process. When leukotriene production is inhibited, bronchodilation is facilitated. Zileuton acts by decreasing tire formation of leukotrienes. Although the result is tire same, montelukast and zafirlukast work in a manner slightly differently from that of zileuton. Montelukast and zafirlukast are considered leukotriene receptor antagonists because they inhibit leukotriene receptor sites in the respiratory tract, preventing airway edema and facilitating bronchodilation. 

Severe acute and chronic allergic and inflammatory processes, keratitis, allergic corneal marginal ulcers, herpes zoster of the eye, iritis, iridocyclitis, chorioretinitis, diffuse posterior uveitis, optic neuritis, sympathetic ophthalmia, anterior segment inflammation... 

Stabilizes lysosomal membrane and prevents the release of proteolytic enzymes released during the inflammatory process... 

Q Impaired Skin Integrity related to the inflammatory process (increased sensitivity to the drug)... 

The diagnosis of PIH is often made by history and clinical presentation. It is characterized by macules and patches of varying shades of hyperpigmentation limited to the sites of inflamed skin lesions. Lesions of the preceding inflammatory process may be present at vari-... 

Testes from the males examined 43 days after the 8-D treatment appeared normal. However, the epididymis was involved in an inflammatory process with sperm granulomas formation. The granulomatous epididymal lesion resembled the lesion seen in auto-immune reaction following bacterial infections or tissue response to foreign bodies (16, 17,... 

Wallace EM, Perkins SJ, Sim RB, Willis AC, Feighery C, Jackson J Degradation of Cl inhibitor by plasmin implications for the control of inflammatory processes. Mol Med 1997 3 385-396. 

Au(CN)2] inhibits the oxidative burst of polymorphonuclear leukocytes and the proliferation of lymphocytes in vitro (both types of cells actively participate in the development and maintenance of inflammatory processes of rheumatoid disease) [71]. It is also far more toxic than gold(I) thiolates to bacteria, plants and animals. 

NF-xB, originally defined as the enhancer of kappa light-chain expression in B lymphocytes, is a hcterodimeric protein that can rapidly activate several genes associated with the inflammatory process (reviewed by Schreck et al., 1992). The DNA binding, nuclear form, of NF-xB is a heterodimer composed of one Rel-A (65 kD) and one p50 (50 kD) subunit. However, both subunits can form homodimers that also have DNA-binding activity. The inactive form of NF-xB in non-stimulated cells is localized to the cytoplasm of resting cells, and is bound to its inhibitor IxB. 

In collaboration with PA Baeuerle (Freibuig), active NF-xB has been detected immunohistochemically in rheumatoid synovium by using a polyclonal antibody directed against the Rel-A NLS subunit of NF-xB (M.L. Kus, unpublished observations). The antibody employed in these studies was considered to be activity specific because IxB sterically masks the NLS sequence. NF-xB activation by ROM in the rheumatoid joint may orchestrate some of the chronic inflammatory processes characteristic of this disease. It is plausible that lL-1 and TNFo generated in the inflamed synovium as well as the up-regulated expression of adhesion molecules may be under the influence of NF-xB. 

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