Carbon Monoxide Protects against Ventilator-induced Lung Injury via PPAR-γ and Inhibition of Egr-1

Abstract

Rationale: Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option. Objectives: This study explores the mechanisms of CO-dependent protection in a mouse model of VILI. Methods: Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of CO (250 ppm). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury, and gene expression. Bronchoalveolar lavage fluid was analyzed for protein, cell and neutrophil counts, and cytokines. Measurements and Main Results: Mechanical ventilation caused significant lung injury reflected by increases in protein concentration, total cell and neutrophil counts in the bronchoalveolar lavage fluid, as well as the induction of heme oxygenase-1 and heat shock protein-70 in lung tissue. In contrast, CO application prevented lung injury during ventilation, inhibited stress-gene up-regulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilation-induced cytokine and chemokine production. Furthermore, CO prevented the early ventilationdependent up-regulation of early growth response-1 (Egr-1). Egr-1-deficient mice did not sustain lung injury after ventilation, relative to wild-type mice, suggesting that Egr-1 acts as a key proinflammatory regulator in VILI. Moreover, inhibition of peroxysome proliferatoractivated receptor (PPAR)-g, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO. Conclusions: Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-g and inhibition of Egr-1.

CO metabolism, sensing, and signaling

“…These data are consistent with the role of HO-1 or Hsp70 as inducible stress proteins that are upregulated as a consequence of systemic stress and inflammatory tissue injury [26]. Therefore, it has been suggested that both HO-1 and Hsp70 are markers of cellular or organ injury, whose expression is precluded by anti-inflammatory protection afforded by exogenous CO treatment [147].…”

“…The upregulation of heat shock factor-1 and Hsp70 expression by CO has been proposed to mediate CO-dependent anti-inflammatory effects in a murine endotoxemia model. Both HO-1 and Hsp70 are upregulated in lung tissue in response to mechanical ventilation, and the application of CO during mechanical ventilation prevents the induction of both genes [147]. These data are consistent with the role of HO-1 or Hsp70 as inducible stress proteins that are upregulated as a consequence of systemic stress and inflammatory tissue injury [26].…”

“…In response to activation by ischemic stress, Egr-1 propagates deleterious responses leading to injury, by controlling the expression of critical genes involved in the regulation of inflammation, coagulation, and vascular permeability [146]. Thus, inhaled CO at low concentrations may represent a promising future therapeutic option for the reduction of VILI [147]. Whether these and other protective effects of CO application observed in animal models of lung injury can be extrapolated to the treatment of patients is the subject of ongoing clinical trials (www.clinicaltrials.gov) [147].…”

“…Thus, inhaled CO at low concentrations may represent a promising future therapeutic option for the reduction of VILI [147]. Whether these and other protective effects of CO application observed in animal models of lung injury can be extrapolated to the treatment of patients is the subject of ongoing clinical trials (www.clinicaltrials.gov) [147].…”

Heme Oxygenase-1/Carbon Monoxide

“…Since its discovery four decades ago (1,2), the heme oxygenase (HO) enzyme system continues to fascinate researchers across many areas of basic and clinical sciences, interconnecting basic science fields (e.g., molecular cell biology and genetics, pharmacology) with modern medical disciplines such as critical care (3)(4)(5), pulmonology (6,7), cardiology (8,9), exercise physiology (10), and transplant immunology (11)(12)(13). This diversity of perspectives on a single enzyme is a reflection of the ubiquitous nature of heme oxygenase-1 (HO-1) as an inducible stress response and critical mediator of cellular homeostasis (14,15).…”