Effects of inhaled carbon monoxide on acute lung injury in mice

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of morbidity and mortality in the intensive care unit, but despite continuing research few effective therapies have been identified. In recent years, inhaled carbon monoxide (CO) has been reported to have cytoprotective effects in several animal models of tissue injury. We therefore evaluated the effects of inhaled CO in three different in vivo mouse models of ALI. Anesthetized C57BL/6 mice were ventilated with oxygen in the presence or absence of CO (500 parts per million) for 1 h before lung injury was induced by lipopolysaccharide (LPS) or oleic acid (OA) administration. Ventilation was then continued with the same gases for a further 2-3 h, with hemodynamic and respiratory parameters monitored throughout. Intratracheal LPS administration induced lung injury with alveolar inflammation (increased lavage fluid neutrophils, total protein, and cytokines). In contrast, intravenous LPS induced a predominantly vascular lung injury, with increased plasma TNF and increased neutrophil activation (surface Mac-1 upregulation and L-selectin shedding) and sequestration within the pulmonary vasculature. Intravenous OA produced deteriorations in lung function, reflected by changes in respiratory mechanics and blood gases and lavage fluid neutrophil accumulation. However, addition of CO to the inspired gas did not produce significant changes in the measured physiological or immunological parameters in the mouse models used in this study. Thus the results do not support the hypothesis that use of inhaled CO is beneficial in the treatment of ALI and ARDS. cytokines; lipopolysaccharide; oleic acid; neutrophil recruitment; pulmonary inflammation ACUTE LUNG INJURY (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are major causes of mortality and morbidity in the intensive care unit. These syndromes are characterized by the development of hypoxemia, alveolar-capillary barrier damage, and pulmonary inflammation, occurring within hours to days of a predisposing insult, which may be of either pulmonary (e.g., pneumonia, aspiration of gut contents) or extrapulmonary (sepsis, acute pancreatitis) nature (32). Despite intense research, few studies have identified therapies that show a beneficial impact on the outcome of ALI, with the exception of the use of lung protective ventilatory strategies (1, 2).Carbon monoxide (CO) has long been known in biology and medicine as a toxic compound, due to its ability to bind hemoglobin with a much higher affinity than oxygen (25). Despite this image as a deadly gas, recent evidence indicates that CO may in fact have a cytoprotective function at low doses. CO is endogenously produced during heme metabolism by the enzyme heme oxygenase, which is one of the major antioxidant cytoprotective enzymes within the body (17,22). Several investigators have reported that exogenously administered CO by inhalation may exert anti-inflammatory effects, providing protection in various animal models of tiss...

Low-dose carbon monoxide treatment attenuates early pulmonary neutrophil recruitment after acid aspiration

“…Similar to our results, one study demonstrated that CO obtunded neutrophil recruitment after 4 h of mechanical ventilation; however, the direct injury was first primed with intravenous LPS, and progression of the injury beyond 4 h was not examined (7). In a study with conflicting results, pretreatment followed by continuous treatment with CO for 4 h did not affect lung inflammation or pulmonary neutrophil activation after direct exposure to intratracheal LPS (10). As suggested in that study, the lack of effectiveness may have been due to the severity and/or hyperacute response of the LPS model.…”

“…The majority of pulmonary studies has demonstrated efficacy with 250 (4,7,22,28,29) or 500 (5, 10, 36) ppm of CO delivered by either mechanical ventilation or spontaneous inhalation (12). Many of these studies use protocols that involve pretreatment with CO (4,10,22,29). Our study used the highest of the commonly reported doses without a pretreatment because this would be more relevant to the majority of clinical aspiration cases.…”

“…These apparently beneficial results have primarily been documented in models of lung injury involving exposure to an insult over several hours to days. When a more severe, hyperacute injury was addressed in one study, CO exposure had no effect on the lung inflammation induced within four hours of either LPS or oleic acid administration (10). The contrasting results from these models suggest that additional studies are needed to validate the effectiveness of exogenous CO therapy in acute lung injury.…”

Physiologic, Biochemical, and Imaging Characterization of Acute Lung Injury in Mice

“…Because neutrophils did not appear in the BAL of mice given Etx alone (Figure 6), and given that neutrophils were frequently found to be adherent to the endothelium of small parenchymal vessels (Figure 4), we believe these findings suggest that Etx-induced neutrophil influx into the lungs was limited to vascular sequestration. Using a dose of Etx that was 1/20th that used in our study, Ghosh and coworkers (29) recently arrived at a similar conclusion. In contrast, neutrophil penetration into the alveolar space after OA (with or without Etx) appears to be the result of either a breach in the alveolocapillary barrier or the establishment of a chemokine gradient caused by epithelial tissue damage.…”

CCAAT/Enhancer-Binding Protein Mediates Carbon Monoxide–Induced Suppression of Cyclooxygenase-2

“…Although many of these reports point toward an anti-inflammatory function of CO in many systems, we still poorly understand the increasingly complex regulation and function of CO in pathophysiologic states. Recent studies suggesting the lack of cytoprotective effect of CO in some systems highlight this complexity (51)(52)(53). This current study attempts to examine one mechanism by which CO may regulate the inflammatory responses.…”