The lung is the major site that produces nitric oxide to induce acute pulmonary oedema in endotoxin shock

1. The present study was undertaken to determine the locus of nitric oxide (NO) production that is toxic to the lung and produces acute pulmonary oede ma in endotoxin shock, to examine and compare the effects of changes in lun g perfusate on endotoxin-induced pulmonary oedema (EPE) and to evaluate the involvement of constitutive and inducible NO synthase (cNOS and iNOS, resp ectively). 2. Experiments were designed to induce septic shock in anaesthetized rats w ith the administration of Escherichia coli lipopolysaccharide (LPS). Exhale d NO, lung weight (LW)/body-weight (BW) ratio, LW gain (LWG) and lung histo logy were measured and observed to determine the degree of EPE 4 h followin g LPS. The EPE was compared between groups in which LPS had been injected e ither into the systemic circulation or into the isolated perfused lung. The lung perfusate was altered from whole blood to physiological saline soluti on (PSS) with 6% albumin to test whether different lung perfusions affected EPE. Pretreatment with various NOS inhibitors was undertaken 10 min before LPS to investigate the contribution of cNOS and iNOS to the observed effec ts. 3. Endotoxin caused profound systemic hypotension, but little change in pul monary arterial pressure. The extent of EPE was not different between that induced by systemic injection and that following administration to isolated lungs preparations. Replacement of whole blood with PSS greatly attenuated (P < 0.05) EPE. In blood-perfused lungs, pretreatment with NOS inhibitors, such as N-<omega>-nitro-L-arginine methyl ester, aminoguanidine and dexame thasone, significantly prevented EPE (P < 0.05). 4, The major site of NO production through the whole blood is in the lung. The NO production mediated by the iNOS system is toxic to the endothelium i n the pulmonary microvasculature. Inhalation of NO for patients with sepsis may be used with clinical caution. Therapeutic consideration of lung extra corporeal perfusion with PSS and pharmacological pretreatment with iNOS inh ibitors may be warranted.