The Regulation of Proresolving Lipid Mediator Profiles in Baboon Pneumonia by Inhaled Carbon Monoxide

Abstract

Strategies for the treatment of bacterial pneumonia beyond traditional antimicrobial therapy have been limited. The recently discovered novel genus of lipid mediators, coined "specialized proresolving mediators" (SPMs), which orchestrate clearance of recruited leukocytes and restore epithelial barrier integrity, have offered new insight into the resolution of inflammation. We performed lipid mediator (LM) metabololipidomic profiling and identification of LMs on peripheral blood leukocytes and plasma from a baboon model of Streptococcus pneumoniae pneumonia. Leukocytes and plasma were isolated from whole blood of S. pneumoniae-infected (n = 5-6 per time point) and control, uninfected baboons (n = 4 per time point) at 0, 24, 48, and 168 hours. In a subset of baboons with pneumonia (n = 3), we administered inhaled carbon monoxide (CO) at 48 hours (200-300 ppm for 60-90 min). Unstimulated leukocytes from control animals produced a proresolving LM signature with elevated resolvins and lipoxins. In contrast, serum-treated, zymosan-stimulated leukocytes and leukocytes from baboons with S. pneumoniae pneumonia produced a proinflammatory LM signature profile with elevated leukotriene B4 and prostaglandins. Plasma from baboons with S. pneumoniae pneumonia also displayed significantly reduced LM-SPM levels, including eicosapentaenoic acid-derived E-series resolvins (RvE) and lipoxins. CO inhalation increased levels of plasma RvE and lipoxins relative to preexposure levels. These results establish the leukocyte and plasma LM profiles biosynthesized during S. pneumoniae pneumonia in baboons and provide evidence for pneumonia-induced dysregulation of these proresolution programs. Moreover, these SPM profiles are partially restored with inhaled low-dose CO and SPM, which may shorten the time to pneumonia resolution.

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

“…200 Current studies have evaluated the therapeutic potential of CO using an S. pneumoniae model of pneumonia in baboons. 55 Plasma obtained from S. pneumoniae infected baboons displayed significantly reduced levels of lipid mediator/specialized pro-resolving mediators (SPM), including eicosapentaenoic acid-derived E-series resolvins (RvE) and lipoxins, suggesting that pneumonia can deregulate pro-resolution programs in baboons. In these animals, CO inhalation increased the levels of plasma RvE and lipoxins relative to control levels.…”

“…In these animals, CO inhalation increased the levels of plasma RvE and lipoxins relative to control levels. These results suggested that altered SPM profiles during pneumonia can be partially restored with inhaled low-dose CO. 55 …”

“…In this regard, application of CO has demonstrated tissue protective effects in models of acute inflammation and organ injury. 28, 44 These studies, using inhaled CO gas, include endotoxemia, 45–47 hyperoxia-induced ALI, 48–49 ventilator-induced lung injury (VILI), 50–52 sepsis and pneumonia, 53–55 I/R injury 56–57 , vascular injury and disease, 58–60 and organ transplantation 58,61–83 ( see Table 3 for representative summary). The protective effects observed in these models were attributed to the effects of CO on apoptosis, cell proliferation, inflammation and immunomodulation.…”

Gaseous mediators in resolution of inflammation

“…Chiang et al [105] reported that inhaled CO markedly reduced neutrophil infiltration into the peritoneum of mice, and increased heme oxygenase activity. They also showed a dramatic shift in the production of pro-resolving mediators: increased production of resolvin D 1 and maresin 1, and decreased production of leukotriene B 4 .…”

The resolution of inflammation: New mechanisms in patho-physiology open opportunities for pharmacology

“…The reason behind this missed opportunity lies in part to technical requirements; for instance, metabololipidomic analyses are just now emerging in high profile analytical translational studies [9]. In similar part, this lack of knowledge is consequent to ignorance and simply the refuse to appreciate the physiological relevance of resolution.…”