ABSTRACT
Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression.
Subject(s)
Animals , Male , Rats , Blood Pressure , Carbon Dioxide/blood , Cardiac Output , Combined Modality Therapy , Endotoxemia/complications , Functional Residual Capacity , Immunohistochemistry , Leukocytes, Mononuclear/pathology , Lipopolysaccharides/pharmacology , Lung/enzymology , Lung Compliance , Lung Volume Measurements , Neutrophils/pathology , Nitric Oxide Synthase Type II/metabolism , Oxygen/blood , Positive-Pressure Respiration/adverse effects , Pulmonary Atelectasis/etiology , Rats, Sprague-Dawley , Thoracotomy/adverse effectsABSTRACT
Objectives To explore ventilation induced cytokine production and the role of oxidant stress in lung stretch. Methods Both in vitro and in vivo models of ventilator-induced lung injury (VILI) were used. Alveolar epithelial cells were stretched in vitro to mimic the lung injury in VILI. Rats were ventilated at large tidal volume to produce ventilator-induced lung injury in vivo. A total of 23 inflammatory cytokines were screened with micro gene array in stretched alveolar epithelial cells. Cytokines found to have up-regulated in cells were measured in serum and lung tissue of rats exposed to large tidal volume ventilation. For investigating the intracellular pathway of cytokine up-regulation in VILI, exogenous TNF-? or H_ 2O_ 2 was added to culture media of alveolar epithelial cells. Cytokines were then measured. To explore the role of oxidant stress in VILI, N-acetylcysteine (NAC), as an anti-oxidant, was used in vitro and in vivo. Results We found that transforming growth factor-?_1 (TGF-?_1 and transforming growth factor-?_2 (TGF-?_2) were up-regulated in stretched alveolar epithelial cells and also in serum of rats with large tidal volume ventilation. Tumor necrosis factor-? (TNF-?) had no effects on TGF-? production in alveolar epithelial cells. Exogenous H_ 2O_ 2, as an oxidant, increased TGF-? production in alveolar epithelial cells. NAC, an anti-oxidant, decreased stretch induced TGF-? production, along with a down-regulation of oxidant injury. NAC also blocked the up-regulation of TGF-? in in vivo model of VILI. Conclusion TGF-?_1 and TGF-?_2 were up-regulated in VILI. Oxidant injury mediated up-regulation of TGF-? in VILI. NAC, which attenuated oxidant injury and blocked TGF-? up-regulation in VILI, could be a future therapeutic strategy in VILI.