Mitogen-activated protein kinases are involved in multiple cascades of serine/threonine and tyrosine phosphory-lating reactions that mediate diverse cellular responses to growth factors, physical stress, and cytokines. The most studied MAPKs in mammalian cells are extracellular signal-related kinases (ERK 1/2), c-jun N-terminal kinases (JNK), and p38 proteins. Although ERK 1/2 is mainly known for its role in cell growth and p38 MAPK plays a major role in cellular responses to stress and injury, both have been implicated in the regulation of vascular endothelial permeability. A typical case is seen in endothelial cells or intact microvas-culature subjected to VEGF stimulation: Inhibition of ERK 1/2 with the ERK kinase inhibitor PD98059 or inhibition of p38 with SB203580 blocks VEGF-induced increases in permeability. In addition to the growth factor, many inflammatory agonists, including histamine, thrombin, hydrogen peroxide, and intracellular calcium elevating agents, are able to phosphorylate ERK 1/2. In parallel, the same types of substances have been found to induce endothelial cytoskeletal contraction and junctional barrier failure through a p38-related mechanism. Clearly, activation of either the ERK 1/2 or the p38 pathway can cause changes in endothelial barrier function; however, their relative contribution may vary depending on the form of stimulation, type of vessels, and duration of observations.
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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.