Endothelial pathomechanisms in acute lung injury

Abstract

Acute lung injury (ALI) and its most severe extreme the acute respiratory distress syndrome (ARDS) refer to increased-permeability pulmonary edema caused by a variety of pulmonary or systemic insults. ALI and in particular ARDS, are usually accompanied by refractory hypoxemia and the need for mechanical ventilation. In most cases, an exaggerated inflammatory and pro-thrombotic reaction to an initial stimulus, such as systemic infection, elicits disruption of the alveolo-capillary membrane and vascular fluid leak. The pulmonary endothelium is a major metabolic organ promoting adequate pulmonary and systemic vascular homeostasis, and a main target of circulating cells and humoral mediators under injury; pulmonary endothelium is therefore critically involved in the pathogenesis of ALI. In this review we will discuss mechanisms of pulmonary endothelial dysfunction and edema generation in the lung with special emphasis on the interplay between the endothelium, the immune and hemostatic systems, and highlight how these principles apply in the context of defined disorders and specific insults implicated in ALI pathogenesis.

Fig. 1

Major pulmonary endothelial functions in health: The structure of pulmonary microvessels and endothelial cells is adapted in such a way as to enable efficient gas exchange of the entire cardiac output at baseline and under exertion. To this end, permeability and vascular tone are kept low and perfusion is matched to ventilation by synthesis and release of several vasoactive compounds such as angiotensin II (AT II), prostacyclin (PGI₂), thromboxane (Tx) A₂, nitric oxide (NO), and endothelin-1 (ET-1). The high vascular compliance of the lung enables it to act as a blood reservoir. Regulation of coagulation and thrombolysis and promotion of hemofluidity by a number of systems aids in maintaining rapid and unobstructed blood flow. In addition, lung endothelial cells (EC) are metabolically highly active, expressing enzymes (such as angiotensin converting enzyme, endothelin converting enzyme, nucleotidases, NO synthase and lipoprotein lipase), receptors, and signal transduction molecules, and synthesizing anti-coagulant and hemostatic factors. Other important functions of lung EC include removal and biotransformation of drugs, participation in immune reactions, binding of immune complexes, internalization of microorganisms and blood components such as leukocytes and platelets. RBC: red blood cells, PMN: polymorphonuclear granulocytes; VSMC: vascular smooth muscle cells, Plt: platelets, dark blue circles: albumin; light blue circles: water. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Endothelial responses in acute lung injury: EC respond to a variety of insults by converting from an anti-adhesive, low permeability barrier to an adhesive, high permeability cell layer, as described in detail in the text. Common endothelial insults include microbes (e.g., bacteria, viruses, protozoa), hyperoxia, radiation, immune complexes, drugs, ischemia/reperfusion, toxins, mechanical stretch and microemboli. Adhesion molecules on the surface of EC orchestrate transmigration of circulating immune cells, which secrete microbicidal and cytotoxic substances such as oxygen free radicals and proteolytic enzymes. Increased endothelial permeability and vascular tone is mediated by vasoactive substances, including thrombin, angiotensin II (AT II), endothelin-1 (ET-1), thromboxane (Tx) A₂, tumor necrosis factor-α and interleukin-8, which are secreted by a number of cell types (EC, platelets, neutrophils, airway epithelia, macrophages). The rationale for these responses seems to be the clearance of infectious agents and damaged host cells; however, life-threatening pulmonary dysfunction and respiratory failure can occur as a consequence of lung flooding and hemodynamic compromise. These alterations trigger a set of anti-inflammatory and repair processes, which, in many cases, successfully restore vascular integrity. RBC: red blood cells, PMN: polymorphonuclear granulocytes; VSMC: vascular smooth muscle cells, Plt: platelets, dark blue circles: albumin; light blue circles: water. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)