Postreperfusion inflammation: a model for reaction to injury in cardiovascular disease

Abstract

In the preceding section various strategies to interdict postreperfusion inflammatory injury of the myocardium were proposed; effectively the strategies were aimed at specific targets such as stimuli which control cell motility, mechanisms of alteration of cell phenotype, and the induction of cell adhesion and proliferation. It is of interest to see how similar these targets would be if one were to attempt a cell biological approach to vascular injury which results in subintimal hyperplasia. In the latter, cells in the media adopt a phenotype which allows cell migration in the direction of a gradient (presumably chemotactic) which directs them to the subintima which is the site of injury. This motility is associated with the expression in these cells of non-muscle myosin and beta actin, both of which are implicated in the motility of leucocytes. Another similarity between acute inflammation and subintimal hyperplasia relates to the role of cellular adhesion as an important determinant of cell motility. As reviewed above, leucocyte motility involves cell adhesion mediated by a class of molecules termed leucocyte integrins (beta 2 integrins) which vary in their alpha subunits and share CD18 as a common beta subunit (CD11a/CD18 = LFA-1, CD11b/CD18 = Mac-1). The activation and inactivation of these integrins is associated with a high and low affinity state, and motility is effected by the cycling of high and low affinity states as well as by cytoskeleton mediated redistribution of adhesion molecules on the leucocyte membrane. In similar fashion, the migration of medial cells and macrophages to the subintima is associated with specific adhesion to extracellular matrix. This adhesion is mediated by similar classes of integrins containing varying alpha subunits and common beta subunits (in this case beta 1 or beta 3) that have been also shown to undergo activation and inactivation cycles yielding high and low affinity states. The similarities between these integrin mediated adhesion events in leucocytes and in the vascular cells is further emphasised by the fact that leucocytes also contain beta 1 integrins; in fact monocytes and T-lymphocytes express a beta 1 integrin (VLA-4) which supports transmigration out of the vascular space via its interaction with VCAM-1 as an alternative to beta 2 integrin-ICAM-1 adhesion. Substantial evidence suggests that integrin mediated adhesion also functions as a transducer of cell secretion of matrix proteins, growth factors, and cytokines from smooth muscle cells, tissue macrophages, transmigrated leucocytes, and endothelial cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Matrix-Dependent Mechanism of Neutrophil-Mediated Release and Activation of Matrix Metalloproteinase 9 in Myocardial Ischemia/Reperfusion

“…[1][2][3][4][5][6][7][8] One cellular response that might favor tissue repair is early resorption of denatured matrix proteins. Neutrophil-derived MMP-9 is stored in tertiary granules and released on chemotactic stimulation.…”

Cardiac Myocytes Produce Interleukin-6 in Culture and in Viable Border Zone of Reperfused Infarctions

“…Inflammation plays an important role in the healing of tissue after injury. [1][2][3][4][5][6][7][8][9] However, there is evidence that the accelerated inflammatory response may also extend tissue injury. Clinical and experimental studies showed that the inflammatory response to myocardial infarction is associated with the induction of cytokines such as tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, and IL-6, which are thought to act in a "cascade fashion."…”

Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress

“…1 Extensive investigations into the pathophysiology of many clinically relevant major tissue injuries, e.g., myocardial infarction, stroke, organ transplantation, revealed that the inevitable early recruitment of neutrophils into the tissue may not only remove necrotic cells, but also may cause damage to healthy cells. 2,3 Thus, neutrophils can considerably aggravate the initial injury and contribute to long-term morbidity and mortality. Because of the potential detrimental effects of neutrophils in many clinical situations, various aspects of the basic mechanisms of neutrophil accumulation at an inflammatory site and the molecular mechanisms of injury have been subject to extensive investigation during the last decade.…”