Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice.

Nora Jahn,Maria T Voelker,Cornelius J Busch,Marleen J A Koel-Simmelink,Daniel D Oswald,Charlotte E Teunissen,Regis R Lamberts,Stephan A Loer,Udo X Kaisers,Thilo Busch,Jörg Weimann

doi:10.1186/s12931-015-0274-7

Abstract

BackgroundInhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it’s biochemical mechanisms and effects on inflammatory reactions.MethodsMice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured.ResultsHPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3rd and 6th hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines.ConclusionLow-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression.

Highlights

Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV)
Preservation of HPV during experimental sepsis was achieved by administration of reactive oxygen species scavengers, by inhibition of nitric-oxide-synthase 2 (NOS-2) with subsequent nitric oxide (NO) production or inhibition of the soluble guanylate cyclase as a molecular target of NO [5, 11, 15, 16]
Baseline pulmonary artery pressure (PAP) was not altered by CO, independently of time and duration of CO exposure

Summary

Introduction

Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). Hypoxic pulmonary vasoconstriction (HPV) represents the main physiological mechanism to match ventilation to perfusion in the lungs and is crucial for appropriate systemic oxygenation [1, 2]. Experimental endotoxemia impairs HPV in several animal models, with increased production of cytokines and nitric oxide (NO) by the inducible nitric-oxide-synthase 2 (NOS-2) being responsible for loss of HPV [5, 11,12,13,14,15]. Preservation of HPV during experimental sepsis was achieved by administration of reactive oxygen species scavengers, by inhibition of NOS-2 with subsequent NO production or inhibition of the soluble guanylate cyclase as a molecular target of NO [5, 11, 15, 16]

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Results