Sites of inflammation

Human bodies are constantly exposed to a plethora of bacteria, viruses, and other inflammatory substances. To combat these infections and toxic agents, the body has developed a carefully regulated inflammatory response system. Part of that response is the orderly migration of leukocytes to sites of inflammation. Leukocytes literally roll along the vascular wall and into the tissue site of inflammation. This rolling movement is mediated by reversible adhesive interactions between the leukocytes and the vascular surface. 

An atherosclerotic lesion consisting of a fibrotic cap surrounding a lipid-rich core. The lesion is the site of inflammation, lipid accumulation, and cell death. Also know as an atheroma. 

Increased accumulation of liposomes, especially small liposomes, has been reported to occur at sites of inflammation (Williams et al., 1986) and in tumors (Turner et al., 1988 Gabizon and Papahadjopoulos, 1988) (cf. Sec. VI.B). However, it is well established that endo-cytosis of liposomes by MPS cells, primarily those located in liver and spleen, accounts for most of the uptake of liposomes—and, in general, uptake of particulate matter—from the blood circulation. 

Although atherosclerosis and rheumatoid arthritis (RA) are distinct disease states, both disorders are chronic inflammatory conditions and may have common mechanisms of disease perpetuation. At sites of inflammation, such as the arterial intima undergoing atherogen-esis or the rheumatoid joint, oxygen radicals, in the presence of transition-metal ions, may initiate the peroxidation of low-density lipoprotein (LDL) to produce oxidatively modified LDL (ox-LDL). Ox-LDL has several pro-inflammatory properties and may contribute to the formation of arterial lesions (Steinberg et /., 1989). Increased levels of lipid peroxidation products have been detected in inflammatory synovial fluid (Rowley et /., 1984 Winyard et al., 1987a Merry et al., 1991 Selley et al., 1992 detailed below), but the potential pro-inflammatory role of ox-LDL in the rheumatoid joint has not been considered. We hypothesize that the oxidation of LDL within the inflamed rheumatoid joint plays a pro-inflammatory role just as ox-LDL has the identical capacity within the arterial intima in atherosclerosis. 

Treatment of acute episodes of ulcerative colitis is dictated by the severity and extent of disease, and first-line therapy of mild to moderate disease involves oral or topical aminosalicylate derivatives. Topical suppositories and enemas are preferred for active distal UC (left-sided disease and proctitis), as they deliver mesalamine directly to the site of inflammation. Topical mesalamine is superior to both topical corticosteroids and oral aminosalicylates for inducing remission in active mild to moderate UC.1,33,34 Enemas are appropriate for patients with... 

Mucins are also thought to act in cooperation with trefoil proteins in the protection and repair of the epithelium (Kindon et al., 1995). Trefoil factors are expressed along the GI tract and increased levels are noted near sites of inflammation and ulcerative lesions (Babyatsky et al., 1996). Furthermore, it has been demonstrated that mouse intestinal trefoil factor may play a role in the alteration of the physicochemical nature of GC mucins during N. brasiliensis infection (Tomita et al., 1995). Perhaps in GI nematode parasite infection mucins are not aiding in the host s protective expulsion of the parasite, but rather are functioning in the repair of the damaged intestinal epithelium. 

T cell activation in the lamina propria is associated with epithelial cell shedding, leading to loss of villi. It has been postulated that this is mediated by increased production of matrix metalloproteases (MMP), which, by degrading the lamina propria matrix, represent a major pathway by which T cells cause injury in the gut (Pender et al., 1997). Production of MMPs also facilitates movement of cells out of the vasculature into sites of inflammation and contributes substantially to the degradation of connective tissue during inflammatory disease (Stetler-Stevenson, 1996). Furthermore, MMPs are required for the release of soluble TNF-a from its membrane... 

Elevated ET-1 in SCA patients, even in the steady state, may play an important role in the dehydration of sickle erythrocytes and the resulting enhanced intra-erythrocytic HbS polymerization. Indeed, it has been shown that ET-1 activates Ca2+- gated K+ channels in mouse erythrocytes [34]. ET-1, as a pro-inflammatory agonist, has been shown to induce the production of inflammatory cytokines by monocytes. One of the cytokines, namely TNFa enhances the adherence of sickle erythrocytes to vascular endothelium [35]. In addition, endothehns upregulate the expression of endothelial adhesion molecules such as ICAM-l, VCAM-1 and E-se-lectin, which participate in the recruitment of white cells to the site of inflammation. The overall conclusions that can be drawn from these data is that ET-1 plays a critical role in the vasospasm and inflammation that result in VOC. The major effect of HU in ameliorating the clinical symptoms of SCA likely results from its ability to inhibit the chronically activated ET-1 expression in SCA patients. 

Although the pathogenesis of inflammatory bowel disease (IBD) remains unclear, increasing evidence suggests that the enteric microflora plays a central role in this process. The distal ileum and the colon are the areas with the highest bacterial concentrations and represent the sites of inflammation in IBD similarly pouchitis appears to be associated with bacterial overgrowth and dysbiosis. 

Induction of expression of various adhesion molecules on the surface of vascular endothelial cells. These act as docking sites for neutrophils, monocytes and lymphocytes, facilitating their accumulation at local sites of inflammation. 

Peripheral inflammation increases prostanoid levels at the site of inflammation and this contributes directly to inflammation and peripheral sensitization (prostanoids and inflammation are discussed in Ch. 33). Peripheral inflammation also increases central prostanoid levels as a result of the central induction of COX-2, to mediate widespread changes in pain sensitivity as well as fever, anorexia, altered mood and sleep patterns [19]. 

Vasoactive substances (histamine, kinins, prostaglandins) are released at sites of inflammation, increasing blood flow and vascular permeability. This causes edema, warmth, erythema, and pain and makes it easier for granulocytes to pass from blood vessels to sites of inflammation. 

The superoxide anion (O2 ) exhibits numerous physiological toxic effects including endothelial cell damage, increased microvascular permeability, formation of chemotactic factors such as leukotriene B4, recruitment of neutrophils at sites of inflammation, lipid peroxidation and oxidation, release of cytokines, DNA singlestrand damage, and formation of peroxynitrite anion (ONOO-), a potent cytotoxic and proinflammatory molecule generated according to equation 7.210 ... 

Gallium is non-essential, but on account of the similarity between Ga3+ and Fe3+ it binds to iron transport and storage proteins such as transferrin and ferritin. The radioactive isotope of gallium, 67Ga, concentrates to a large extent in many tumours and at sites of inflammation and infection, and since many tumours overexpress the transferrin receptor it can be used for tumour imaging. 

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