Carbon Monoxide Modulates the Innate Immune Response to Bacterial Lung Infection

Abstract

Carbon monoxide (CO) is generated endogenously in all mammalian cells by the enzyme Heme Oxygenase-1 (HO-1). HO-1 is primarily responsible for heme metabolism but is also vital for the host’s ability to appropriately respond to stress. While previously thought to be a functionless byproduct, CO is now accepted as possessing critical physiological and therapeutic properties at low concentrations. Treatment with low doses of exogenously-delivered inhaled CO (250 ppm; 0.025%) for as little as 1h confers protection in preclinical animal models of acute lung injury, ischemia/reperfusion injury, sepsis and organ transplantation. While the mechanism(s) of protection are poorly understood, studies indicate that CO modulates inflammation and regulates innate immune responses. We tested the hypothesis that exposure to CO would enhance bacterial clearance in a mouse pneumonia model and that the mechanism involves in part changes in macrophage and neutrophil phenotypes that become more effective at killing bacteria. Employing a mouse model of bacterial pneumonia, we show that CO augments bacterial clearance in the lung airway at 24hr in CO versus air-treated animals. Cells that were collected from the airway by bronchoalveolar lavage were analyzed for phenotypic changes using CyTOF, a multi-dimensional single cell analysis tool. CO treated, infected mice showed unique populations of cells that were not observed in controls, including significant numbers of CD68+ neutrophils and macrophages that expressed higher TLR2 and CD64 levels compared to control and may explain the enhanced bacterial killing. Collectively, my results demonstrate that CO augments bacterial clearance from the lung and does so in part by modulating immune cell function. Future studies will examine how these particular cell populations contribute to protection against bacterial lung infection.