Microvascular Permeability in Experimental Sepsis: Mechanisms, Modulation and Management

Abstract

Alterations in microcirculatory permeability are characteristic of early tissue injury, and are thought to result from contraction of activated endothelial cells (Fig. 1). A defining hallmark of a number of inflammatory conditions including sepsis and the acute respiratory distress syndrome (ARDS), is the so-called high-permeability interstitial edema of the systemic and pulmonary circulations, respectively [1]. Moreover, tissue edema is an early indicator of tissue dysfunction, prior to organ failure [2]. The extent of edema formation has been associated with impaired gas exchange and arterial hypoxemia in ARDS. Edema may also impair tissue oxygen distribution due to increased intercapillary distances, such that speculation regarding its potential role in exacerbating tissue hypoxia persists despite evidence to suggest a lack of external compression of skeletal muscle microvessels to account for increased capillary density in a rodent model of sepsis [3]. As a result of increased microvascular permeability, the loss of plasma fluid to the interstitial space leads to hypovolemia, with increased sympathetic activation and an imbalance of fluid/electrolyte homeostasis. This exacerbates the persisting hemodynamic instability. Currently, no proven effective pharmacologic therapy is available to reduce increased permeability, although numerous agents are under investigation. Such a drug, with a capillary-permeability reducing effect, would clearly be of great value in the critically ill. The following chapter briefly reviews theories of permeability to macromolecules (i.e., protein), the mediators that bring about these changes, and the mechanisms by which these processes are postulated to occur, in the context of acute inflammation, particularly during sepsis. For a detailed review of theoretical aspects of microvascular permeability, the reader is directed to a recent authoritative text on the subject [4].