Attenuated expression of inducible nitric oxide synthase in lung microvascular endothelial cells is associated with an increase in ICAM-1 expression

Background/Purpose: The molecular and cellular events that regulate inflamm atory lung injury, a major cause of morbidity in surgical patients, remain unclear. The authors hypothesize that nitric oxide (NO) plays an important role in regulating polymorphonuclear cell (PMN)-induced acute lung injury, and further, that attenuated expression of inducible nitric oxide synthase (iNOS) and therefore decreased production of NO by lung microvascular endot helial cells (LMVEC), accelerates inflammation and injury. Methods: LMVEC and aortic EC (AEC) from rat and human were stimulated with lipopolysaccharide (LPS) and cytokines; changes in iNOS mRNA expression and iNOS activity were determined. The role of NO in mediating inflammatory re sponses was evaluated by determining PMN adherence to LMVEC and lung tissue slices in the presence and absence of NOS inhibitors and NO donors. Human LMVEC and AEC were assessed by FACS analysis for ICAM-1 expression, because this is thought to be a critical determinant of PMN adherence. Results: When stimulated with endotoxin and cytokines, rat AEC monolayers e xpress nearly 3-fold more iNOS mRNA than rat LMVEC. The low levels of LMVEC iNOS expression are associated with a 4-fold lower nitrite and nitrate pro duction. Similar trends are seen in human endothelial cells. When iNOS acti vity was blocked, PMN adherence to tumor necrosis factor alpha (TNF alpha)/ LPS-stimulated LMVEC was markedly increased. In contrast, adding a nitric o xide donor to endotoxin/cytokine-stimulated LMVEC monolayers reduced PMN ad herence to near background levels. Similar responses were observed in vivo. Human lung microvascular endothelial cells show a substantially increased level of ICAM-1 upregulation when compared with similarly stimulated human aortic macrovascular endothelial cells. Conclusions: These data indicate that LMVEC express less iNOS and produce l ess NO than AEC. This lower expression and activity of iNOS in LMVEC may be linked to increased expression of ICAM-1. Because ICAM-1 has been shown to be essential for tight PMN adherence, these data suggest that relatively l ow iNOS expression in LMVEC may contribute to a propensity for the lung to be injured by activated PMNs. J Pediatr Surg 36:1136-1142. Copyright (C) 20 01 by W.B. Saunders Company.