Ultrastructure of immediate microvascular lung injury induced by bacterial endotoxin in the isolated, no-deficient lung perfused with full blood.

NOS-2-derived NO is involved in hypotension, vasoplegia, metabolic disorders and lung injury in endotoxic shock. On the other hand, NOS-3-derived NO protects against LPS-induced lung injury. We have previously shown that NO limits lung injury in the isolated blood-perfused rat lung. Here we characterize the ultrastructure of microvascular lung injury induced by LPS in the absence of endogenous NO and summarize our data on the mechanisms of immediate lung response to LPS in the presence and absence of endogenous NO. Injection of LPS (from E.Coli, 300 microg/ml) into the isolated blood-perfused rat lung induced an immediate transient constriction of airways and vessels that was not associated with lung edema and pulmonary microcirculation injury. In contrast, in the presence of the NOS inhibitor L-NAME (300 microg/ml), LPS produced an enhanced constriction of airways and vessels, which was accompanied by profound lung edema and capillary-alveolar barrier injury, as evidenced by optic and electron microscopy. Microvascular lung injury was confirmed by the following findings: edema of pulmonary endothelium with low electronic density of endothelial cytoplasm, presence of protein-rich fluid and numerous erythrocytes in alveolar space, concentric figures of damaged tubular myelin of surfactant (myelin-like bodies), edema of epithelium type I cells with low electronic density of their cytoplasm and alterations in ultrastructure of basal membrane of vascular-alveolar barrier. Interestingly, epithelial type II cells did not show signs of injury. It is worth noting that capillary-alveolar barrier injury induced by L-NAME+LPS was associated with sequestration of platelets and neutrophils in pulmonary microcirculation and internalization of LPS by neutrophils. In conclusion, in the absence of endogenous nitric oxide LPS induces injury of microvascular endothelium and vascular-alveolar barrier that leads to fatal pulmonary edema. Mechanisms of immediate lung response to LPS in presence of NO and those leading to acute microvascular lung injury in response to LPS in absence of NO are summarized. In our view, immediate lung response to bacterial endotoxin represents a phylogenetically ancient host defence response involving complement-dependent activation of platelets and neutrophils and subsequent production of lipid mediators. This response is designed for a quick elimination of bacterial endotoxin from the circulation and is safeguarded by endothelial NO.