Sepsis is a systemic inflammatory response to a local infectious insult. The release of lipopolysaccharide (LPS)
(or comparable bacterial product) into the bloodstream initiates activation of immune cells and subsequent release of inflammatory cytokines that precipitate a number of circulatory disorders. These include decreased systemic vascular resistance, reduced responsiveness to vasoconstrictors and vasodilators at the microvascular level, impaired oxygen utilization, and maldistribution of flow within the capillary bed. Since sepsis can affect endothelial function (e.g., biosynthesis of nitric oxide, permeability), it is possible that sepsis could also affect the capillary-arteriolar communication and, consequently, the feedback pathway of the local blood flow control.
Using the micropipette application approach (Figure 1) in septic rat skeletal muscle (i.e., 24-hour cecal ligation and perforation model of sepsis), we found that sepsis attenuated the arteriolar response to vasodilators applied distally on capillaries. Since this attenuation was more pronounced than the attenuation seen after application of vasodilators directly on the arteriole, we concluded that the capillary sensing/communication was affected by sepsis .
Because of the technical limitations of our in vivo model, we used our in vitro models of communication to tease out the effect of sepsis on capillary sensing and/or communication. Based on the "capillary-like" structure model, LPS (an initiating factor in sepsis) was found to attenuate electro-tonic communication along "capillary" length but not alter the local agonist-induced hyper/depolarization . Thus, capillary communication, rather than capillary sensing, was more likely to be affected by sepsis in vivo. Attenuated communication along the "capillary" could occur via reduced GJ conductance between adjacent endothelial cells or via increased transmembrane conductance (i.e., conductance across cell membrane to extracellular space) of these cells. Based on our endothelial cell monolayer model, LPS was found to reduce GJ conductance, but not alter the transmembrane conductance. Further, this reduction was found to be reversible, protein tyrosine kinase dependent, but protein synthesis and mitogen-activated protein kinase independent . Our subsequent study pinpointed Cx43 as the likely GJ protein to be responsible for the reduced GJ conductance. LPS caused phosphorylation of Cx43 tyrosine residue(s), an event that is generally associated with GJ closure and reduced coupling. Altered tyrosine kinase and phosphatase activities modulated in parallel both LPS-induced phospho-rylation of Cx43 and reduction in GJ conductance. Thus these studies provided evidence that at least one agent of sepsis (i.e., LPS) could affect the capillary-arteriolar communication via reduced gap junctional coupling of endothelial cells .
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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.