Mechanistic considerations on the development of lung edema: Vascular, perivascular and molecular aspects from early stage to tissue and vascular remodeling stage

The purpose of this article is double, to review the mechanisms allowing to control the volume of the extravascular lung water and then to trace a pathophysiological basis for the development of lung edema when such control is lost. Efficient gas diffusion in the air-blood barrier is guaranteed by an extremely low volume of extravascular water, assuring a minimum barrier thickness, and by a perfect matching between alveolar perfusion and ventilation. Low microvascular permeability and dynamic remodeling of the interstitial matrix and of microvessels maintain this equilibrium. Lung cells play a crucial role by acting as early sensors of the dysregulation of lung water balance. When capillary filtration increases due to an increase in microvascular permeability (e.g as in hypoxia), interstitial pressure rises substantially due to the rigidity of the interstitial compartment. This triggers mechano-transduction in lung cells through the expression of lipid microdomains that represent specific signaling platforms. Severe edema occurs as a result of yielding/fragmentation of important link proteins (matrix proteoglycans) to excessive tissue stress. The reparative matrix remodeling is stimulated by FGFβ (Fibroblast Growth Factor β) and KGF (Keratinocyte Growth Factor). In edematous regions the increase in tissue pressure may cause compression of microvessels and associated marked precapillary vasoconstriction, thus resulting in an increase in pulmonary vascular resistances. Vascular remodeling decreases blood flow in edematous regions and favors blood redistribution to normal regions. Pulmonary hypertension is common to all conditions of severe lung edema and is proportional to the extension of the edematous process. In conclusion, it appears tempting to think of pulmonary hypertension as the consequence, rather than the cause, of lung edema which would lead to hypothesize that an excessive fibro-proliferative process in the lung might be interpreted as the response to a chronic condition of high microvascular permeability. © 2012 Bentham Science Publishers.