Effects of inhaled carbon monoxide and glucocorticoids in porcine endotoxin sepsis

Introduction

Recent animal studies have demonstrated that pretreatment with inhaled carbon monoxide (iCO) may exert anti-inflammatory effects in various models of septic tissue injury. In all of these injury models, iCO was administered before the development of injury, and there is no information about whether iCO might act therapeutically (after the disease process has started) to treat established injury. We therefore investigated for the first time the potential beneficial effects of iCO in a porcine sepsis model and the administration of CO after the onset of septic damage because this model is close to clinical reality.

Methods

Five groups of six pigs each (30 pigs), under anaesthesia and mechanical ventilation, were studied. In 24 pigs (four groups), a sepsis model and acute lung injury was created by continuous (20 μg/kg/hour) intravenous infusion of lipopolysaccharide (LPS) for 6 hours. After 2.5 hours of LPS infusion, other groups with six pigs in each either received LPS infusion, received 250 ppm iCO for 3.5 hours continuously, received 3 mg/kg hydrocortisone bolus (steroid), or received both steroid and iCO. For comparison, another healthy control group was studied under anaesthesia and mechanical ventilation. Measurements of haemodynamics, blood gases, respiratory mechanics and biochemistry of organ function (liver, kidney, myocardial) were made intermittently during time course of the experiment. At the end of the 6-hour period, the animals were killed and lung tissue was taken for quantitative histological evaluation (inflammatory cells, edema, haemorrhage) and inflammatory markers (glucocorticoid receptors, TNFα, NF-κB, activator protein 1).

Results

LPS administration induced a dramatic inflammatory injury in lungs, a marked expression in TNFα, NF-κB, activator protein 1, downregulation of glucocorticoid receptors, acute lung injury with pulmonary hypertension and severe deterioration on organ function, respiratory mechanics, and oxygenation. Treatment with steroid and to greater extent with iCO significantly improved the microscopic appearance of the lung while it had no effect on inflammatory markers. In terms of haemodynamics, iCO significantly decreased pulmonary hypertension induced by LPS, without an obvious protective effect on organ function and respiratory mechanics.

Conclusion

The major findings in the current study are that iCO administered after LPS infusion significantly decreased pulmonary hypertension, and attenuated the histological appearance of the lung damage, without an obvious protective effect on organ function and respiratory mechanics.