Mediators that Increase Vascular Permeability

Inflammatory Mediators that Increase Vascular Permeability 

Several mediators have been implicated in the plasma leakage associated with airway inflammation. Most of these mediators have relatively transient effects on vascular permeabUity, because of the existence of mechanisms that limit the duration of their effects. For example, the action of substance P on vascular endothelial ceUs is Umited by the phosphorylation and internalization of neurokinin (Nki) receptors (Bowden et al., 1994a) and by the degradation of substance P by neutral endopeptidase and other enzymes (Umeno et al., 1989 Nadel, 1992 Katayama etal., 1993). 

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Inflammatory Mediators that Increase Vascular Permeability... 

Bradykinin is an endogenous inflammatory substance that increases vascular permeability and produces tissue edema. The kallikrein-kinin system is very rapidly activated following brain injury resulting in the activation of kallikrein that cleaves kininogen to produce bradykinin. The effects of bradykinin are mediated by two different receptors B1 and B2. Very low levels of B1 are found under normal conditions. In contrast, the B2 receptor is constitutively expressed in a wide variety of tissues including the brain and mediates the majority of bradykinin effects (Couture et al., 2001). 

Fig. 2. IgG-mediated systemic versus local anaphylaxis, a IgG-mediated systemic anaphylaxis. When allergen-IgG immune complexes are formed in the circulation, basophils immediately capture them through IgG receptors on their surface and are activated to release PAF, that in turn act on vascular endothelial cells, leading to increased vascular permeability, b Passive cutaneous anaphylaxis. When allergen-IgG immune complexes are formed in the skin, they stimulate tissue-resident mast cells to release chemical mediators such as histamine, leading to local inflammation. 

Deposition of urate crystals in synovial fluid results in an inflammatory process involving chemical mediators that cause vasodilation, increased vascular permeability, complement activation, and chemotactic activity for polymorphonuclear leukocytes. Phagocytosis of urate crystals by leukocytes results in rapid lysis of cells and a discharge of proteolytic enzymes into the cytoplasm. The ensuing inflammatory reaction is associated with intense joint pain, erythema, warmth, and swelling. 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer s disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. 

Mechanism of type I hypersensitivity. Initial exposure to allergen leads to production of IgE by plasma cells differentiated from allergen-specific B cells (not shown). The secreted IgE binds cognate IgE-specific receptors on blood basophils and tissue mast cells. Reexposure to allergen leads to cross-linking of membrane-bound IgE. This union causes degranulation of cytoplasmic granules and release of mediators that induce vasodilation, smooth muscle contraction, and increased vascular permeability. These effects lead to the clinical symptoms characteristic of type I hypersensitivity. 

Glucocorticoids inhibit pathways that normally lead to production of prostaglandins, leukotrienes and platelet activating factor. These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration, fibrin deposition. 

Early work on the effects of JP-8 inhalation in rats showed an inverse relationship between increases in airway epithelial permeability ("TcDTPA clearance) and decreased concentrations of the tachykinin substance P in bronchoalveolar lavage fluid (BALF) (Hays et al. 1995). Substance P has a strong affinity for the neurokinin receptor NK, one of a family of plasma-membrane-bound neurokinin receptors that mediate protective reflex responses—such as bronchoconstriction, increased vascular permeability, vasodilatation, mucus secretion, and enhanced mucociliary activity—to airway exposure to mechanical or chemical irritants. 

A number of factors, including tissue damage, allergic reactions, viral infections, and other inflammatory events, activate a series of proteolytic reactions that generate bradykinin and kallidin in tissues. These peptides contribute to inflammatory responses as autacoids that act locally to produce pain, vasodilation, and increased vascular permeability. Much of their activity is due to stimulation of the release of potent mediators such as prostaglandins, NO, or endothelium-derived hyperpolarizing factor (EDHF). 

As discussed earlier in this chapter (see also Chapter 6 for a detailed discussion of cytokines), there is considerable expression of the cytokines, interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) a by the rheumatoid synovium. TNFa is a proinflammatory cytokine (cell protein) that plays a major role in the pathological inflammatory process of rheumatoid arthritis. TNF is an important mediator of local inflammation, and the release of TNFa from T-cells produces increased vascular permeability, release of nitric oxide with vasodilation, local activation of vascular endothelium, increased expression of adhesion molecules on endothelial blood vessels, and increased platelet activation and adhesion. As TNFa builds up in the joints, it leads to joint inflammation, which ultimately results in joint destruction. Because of its role In the progression of rheumatoid arthritis, methods for rendering TNFa inactive has... 

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