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Granger DN, Senchenkova E. Inflammation and the Microcirculation. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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Inflammation and the Microcirculation.

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The preceding discussion underscores the complexity of the inflammatory response and the diversity in the responses of the microvasculature to this condition. The large and continually expanding body of knowledge on the microcirculation and its contribution to inflammation has revealed the participation of all segments of the microvasculature, i.e., arterioles, capillaries, and venules. The best characterized phenotypic changes that are exhibited by the microvasculature during inflammation include impaired vasomotor function, reduced capillary perfusion, adhesion of leukocytes and platelets, activation of the coagulation cascade and enhanced thrombosis, increased vascular permeability, and an increase in the rate of proliferation of blood and lymphatic vessels. Collectively, these responses appear to be geared toward enhancing the delivery of inflammatory cells to the injured/infected tissue, isolating the region from healthy tissue and the systemic circulation, and setting the stage for tissue repair and regeneration.

It appears that virtually every cell that either resides within or courses through the inflamed region is activated, which allows the cells that have a stake in the outcome of the inflammatory response to make a meaningful contribution. Although these cells are highly specialized, they respond to an inflammatory response in much the same way, i.e., by producing excess amounts of ROS or by releasing cytokines and/or proteases. This redundancy likely serves to amplify the response and achieve an intensity that ensures rapid eradication of an infectious agent. It remains unclear whether any single cell type plays a dominant role in coordinating the microvascular response to inflammation. If such an orchestrator exists, it is likely the endothelial cell. These cells serve as the gatekeeper for the migration of inflammatory cells into the affected tissue, modulate the tone of underlying VSM and hence blood flow, provide an interface for the activation/deposition of coagulation factors and binding of platelets during thrombus formation, and play a critical role in the formation of new blood vessels. While little attention has been devoted to if/how the responses of arterioles, capillaries, and venules are coordinated during inflammation, ECs also appear to be well suited to assume such a function.

Although we have conveniently addressed the microvascular responses to inflammation as separate, independent processes, there is compelling evidence that these events are closely linked and share many chemical mediators and signaling pathways. A growing number of mediators have been identified that have the capacity to elicit most or all of the characteristic vascular responses to inflammation, which supports the view that redundant reinforcing signals are received along the entire length of the microvasculature. Thrombin, for example, which has received most attention for its critical role in the coagulation/thrombosis response, is also able to modulate vasomotor function, leukocyte recruitment, vascular permeability, and angiogenesis. VEGF and some cytokines (e.g., TNF-α) are additional examples of single mediators that can elicit most (if not all) of the characteristic microvascular responses to inflammation. The production, release and/or actions of these pleiotropic mediators also appear to be interdependent. For example, thrombin promotes VEGF production and induces an increased expression of VEGF receptors, while TNF-α can elicit thrombin production. Perhaps the single most important chemical alteration in inflamed tissue that accounts for the subsequent generation of a whole host of inflammatory mediators is the imbalance between ROS and NO species. The fact that virtually every cell involved in the inflammatory response undergoes an oxidative burst underscores the importance of ROS in this process. ROS, like soluble inflammatory mediators, exert pleiotropic actions that serve to further amplify the inflammatory response.

The recent discovery of the multitude of mediators and signaling mechanisms that contribute to the inflammatory response has raised hopes for the development of effective new drugs for the treatment of inflammatory diseases. Drugs that target a specific microvascular response to inflammation, such as leukocyte–endothelial cell adhesion or angiogenesis, have shown promise in both the preclinical and clinical studies of inflammatory disease. Future research efforts in this area are certain to identify new avenues for therapeutic intervention and should reveal whether agents that target a single chemical mediator or multiple mediators with overlapping actions show the most promise for clinical success.

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53371


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