P-selectin mediates the rolling interaction between neutrophils and endothelial cells. But in SHR the adhesion of leukocytes to microvascular endothelium induced by inflammatory mediators under physiologic blood shear rates is reduced (Suematsu et al., 1995). The downregulation of leukocyte adhesion appears to involve both leukocyte- and endothelial cell-dependent mechanisms. The SHR has reduced levels of P-selectin on the endothelial membrane of post-capillary venules. There is also a reduction of the sialyl Lewis X-like carbohydrate structure on the leukocytes.
Attenuation of leukocyte rolling has two important consequences.
• The SHR has a chronically elevated count of circulating leukocytes with enhanced levels of free radical production and cytoplasmic degranulation. The elevation in the number of circulating neutrophils and monocytes may result from demargination of these cells in postcapillary venules by suppression of the selectin-dependent membrane interaction. A similar leukocytosis is encountered in P-selectin gene knockout mice with diminished ability for leukocyte rolling on venular endothelium.
• The SHR exhibits a diminished sensitivity to inflammatory stimuli relative to WKY rats and consequently enjoys a surprising protection against inflammatory mediators. The suppression of a P-selectin mediated adhesion pathway may compromise normal leukocyte response under physiological fluid shear conditions and early steps in tissue and lesion repair.
Endothelial ICAM-1 expression under both constitutive and induced conditions is upregulated in SHR in splanchnic organs but not necessarily in heart or skeletal muscle. Circulating leukocytes adhere to and spread on endothelium with ICAM-1 overexpression under conditions of reduced fluid shear stress and thereby cause a selectin-independent margination of leukocytes.
In contrast to the resistance to inflammation, the SHR is more vulnerable than the WKY rat to hemorrhagic hypotension or acute ischemia and reperfusion (Cerwinka and Granger, 2001). Enhanced numbers of activated leukocytes trapped in the microcirculation during ischemia are associated with increased organ injury and reduced survival. Once exposed to hemorrhagic shock, activated neutrophils in the circulation are trapped in microvessels of the SHR and expose the tissue to greater oxidative stress than in the WKY rat. The SHRs display a greater extent of microvascular protein leakage upon ischemia-reperfusion than WKY.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.