Inflammation Leukocytic migration

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. 

In an important study, Kirton et al. [5] engineered a mouse-human chimeric antibody and demonstrated that this was able to reduce leukocyte migration in various in vitro and in vivo mouse models. In particular, leukocyte migration to the peritoneal cavity was reduced by 40% in the thioglycollate inflammation model using mice expressing human SSAO/VAP-1 protein. The Finnish company Biotie Therapies Corporation, is in clinical development with an antibody to VAP-1 [54],... 

Milk thistle may have anti-inflammatory properties. In vitro, silybin strongly and noncompetitively inhibits lipoxygenase and leukotriene formation. On the other hand, concentrations required to inhibit thromboxane and prostaglandin formation in vivo probably exceed dosing capabilities. Inhibition of leukocyte migration has also been observed in vivo and may be a factor when acute inflammation is present. 

It is of interest how the presently accepted concept of aspirin and aspirinlike compounds involvement with PGs came about. The last of the aspirin theories to arise proposed that aspirin interfered with leukocyte migration to the site of injury, thus inhibiting the inflammatory process. A prostaglandin phase of inflammation, where PGs arose in the exudate of experimentally induced edema after the appearance of histamine and bradykinin, was already known. These two events appeared to coincide in the inflammatory process. Thus, the time was ripe. In studying the mediators responsible for the anaphylactic response in sensitized guinea pig lungs, Piper and Vane (1969) isolated histamine, SRS-A, and a new substance they called rabbit aorta contracting substance (RCS), a very unstable material (1 to 2 min) whose release, and presumably production, was selectively inhibited by aspirin-... 

Higgs, G., Eakins, K., Moncada, S. and Vane, J. (1980). The effects of non-steroidal antiinflammatory drugs on leukocyte migration in carrageenin-induced inflammation. Eur. J. Pharmacol, 68, 81-86... 

FIGURE 6.22 The selectin-ligand interaction recruits leukocytes to the vascular endothelium, which allows them to adhere. Following the inflammatory mediators, leukocytes migrate from the blood vessels toward the focus of inflammation. Source Fasting et al. [89], figure 21. Reproduced with permission of John Wiley Sons. 

Chemokines, c/jemoattractant cytokines, are small (8—14 kDa) proteins that bind to G-protein-coupled receptors composed of seven transmembrane domains (BaggioHni, 1998). The chemokine family encompasses more than 50 members, which can be either homeostatic or inflammatory (Zlotnik Yoshie, 2000). The former are constitutively expressed in certain tissues and have roles in tissue development, such as angiogenesis or neovascularization, or basal leukocyte migration (Rot von Andrian, 2004). In the latter, an infection or other proinflammatory stimulus (TNF-a) will cause the release of chemokines that will direct the recruitment of leukocytes (e.g., neutrophils, monocytes, etc.) toward the site of inflammation (Zlotnik, Burkhardt, Homey, 2011). 

Leukocyte migration is a key event both in host defense against invading pathogens as well as in inflammation. Here we discuss three proteins that specifically interfere with this aspect of the innate immune system CHIPS and FLIPr. 

Numerous in vitro studies and clinical data of IL-8 production in biofluids imply the pathological importance of IL-8 in acute inflammation. However, many scientists did not seriously believe the critical role of IL-8 in leukocyte migration in vivo until we first unveiled that IL-8 was essentially involved in lung reperfusion injury using a specific monoclonal antibody (mAb) against IL-8. 

In addition to its effects on cell growth, CLP elicits antinociceptive and anti-inflammatory activities. Peripheral antinociceptive activity was investigated by acetic acid-induced writhing model. CLP (0.1-100 mcM/kg) inhibited acetic acid-induced abdominal constrictions dose dependently (1C50 = 0.0945). Central antinociceptive activity of CLP was demonstrated in the hot plate test. CLP (100 mcM/kg, p.o.) increased latency time 90, 120, and 150 min after treatment. Similarly, CLP caused an inhibition of nociception in formalin test. Anti-inflammatory activity of CLP was evaluated in capsaicin-induced ear edema and carrageenan-induced peripheral inflammation tests. Following oral administration at a dose of 100 mcM/kg, CLP inhibited capsaicin-induced ear edema by 55.8% and reduced leukocyte migration to the inflammatory sites by 48.3% [61]. 

Futher evidence for the importance of adhesion molecules as targets for antiinflammatory polysaccharides was provided by Dong and Murphy [74, 75]. They showed, using an in vivo mouse model that a glucuronoxylomannan from Cryptococcus neoformans inhibits leukocyte extravasation into sites of acute inflammation. They propose that binding to CD 18 (part of the cell adhesion molecule Mad) on human neutrophils is responsible for the observed inhibition of leukocyte migration. 

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