Inflammatory cells processes

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. 

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... 

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. 

As with UC, the immune activation seen in CD involves the release of many proinflammatory cytokines. Cytokines thought to play major roles in CD are derived from T-helper type 1 cells and include interferon-y, TNF-a, and IL-1, IL-6, and IL-12. TNF-a is a major contributor to the inflammatory process seen in CD. Its physiologic effects include activation of macrophages, procoagulant effects in the vascular endothelium, and increases in production of matrix metallo-proteinases in mucosal cells.9,15 Excessive production of both... 

Corticosteroids have potent anti-inflammatory properties and are used in active IBD to rapidly suppress inflammation. Corticosteroids have favorable effects in modulating several cell types involved in the inflammatory process.20,21 They may be administered systemically or delivered locally to the site of action by altering the drug formulation (Table 16-2). Because these drugs usually improve symptoms and disease severity rapidly, they should be restricted to short-term management of active disease. Long-term use of systemic corticosteroids is... 

Chronic pancreatitis is an inflammatory process that occurs over a long period of time. The inflammation damages the enzyme-producing cells in the pancreas and can also disrupt or destroy the endocrine function of the pancreas by causing diffuse... 

Activated T cells begin releasing cytokines including interleukin-2 (IL-2), interferon-y, (IFN-y), tumor necrosis factor (TNF-a), and others.4,13 Cytokine activity leads to a rapid proliferation and turnover of skin cells, triggering the inflammatory process and the development of psoriatic skin lesions.4,13,14 TNF-a may have a role in disease severity it upregulates endothelial and keratinocyte expression of ICAM-1,... 

Fig. 14.1. The Thl/Th2 balance is central to the regulation of normal wound repair. Tissue injury results in the initiation of an inflammatory response, mediated by a variety of cells and their by-products. Immune cells are recruited and cross-regulate the Thl/ Th2 balance that occurs in response to the cytokine environment. This balance is in turn cross-regulated by the chemokine/chemokine-receptor expression profile, which functions to amplify the inflammatory process. Cells residing in the injured tissue release profibrotic mediators, which promote fibroblast activation, proliferation, and differentiation to the myofibroblast phenotype. Myofibroblasts produce collagen to repair damaged tissue, which is an event that is favored by the inhibition of MMP activity. The Thl/Th2 balance is central to whether a normal or aberrant wound-repair process is established A Thl environment promotes normal tissue resolution (fibrinolysis), whereas a Th2 environment maintains the progression of fibrotic disease (excessive collagen deposition).

At the cellular level, eosinophils, mast cells, alveolar macrophages, lymphocytes and neutrophils recruited to the airways of asthmatics produce a variety of inflammatory mediators, such as histamine, kinins, neuropeptides, and leukotrienes, which lead to airway smooth muscle constriction and obstruction of airflow, and the perpetuation of airway inflammation [20, 21]. An understanding of the inflammatory processes and the molecular pathways of these mediators has led to the development and widespread use of several pharmacologic agents that mitigate airway inflammation and bronchoconstriction. 

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