Evaluation of inhaled carbon monoxide as an anti-inflammatory therapy in a nonhuman primate model of lung inflammation

Abstract

Carbon monoxide (CO) confers anti-inflammatory protection in rodent models of lung injury when applied at low concentration. Translation of these findings to clinical therapies for pulmonary inflammation requires validation in higher mammals. We have evaluated the efficacy of inhaled CO in reducing LPS-induced lung inflammation in cynomolgus macaques. LPS inhalation resulted in profound neutrophil influx and moderate increases in airway lymphocytes, which returned to baseline levels within 2 wk following exposure. CO exposure (500 ppm, 6 h) following LPS inhalation decreased TNF-α release in bronchoalveolar lavage fluid but did not affect IL-6 or IL-8 release. Lower concentrations of CO (250 ppm, 6 h) did not reduce pulmonary neutrophilia. Pretreatment with budesonide, a currently used inhaled corticosteroid, decreased LPS-induced expression of TNF-α, IL-6, and IL-8, and reduced LPS-induced neutrophilia by ∼84%. In comparison, CO inhalation (500 ppm, for 6 h after LPS exposure) reduced neutrophilia by ∼67%. Thus, inhaled CO was nearly as efficacious as pretreatment with an inhaled corticosteroid at reducing airway neutrophil influx in cynomolgus macaques. However, the therapeutic efficacy of CO required relatively high doses (500 ppm) that resulted in high carboxyhemoglobin (COHb) levels (>30%). Lower CO concentrations (250 ppm), associated with anti-inflammatory protection in rodents, were ineffective in cynomolgus macaques and also yielded relatively high COHb levels. These studies highlight the complexity of interspecies variation of dose-response relationships of CO to COHb levels and to the anti-inflammatory functions of CO. The findings of this study warrant further investigations for assessing the therapeutic application of CO in nonhuman primate models of tissue injury and in human diseases. The study also suggests that akin to many new therapies in human diseases, the translation of CO therapy to human disease will require additional extensive and rigorous proof-of-concept studies in humans in the future.

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

“…(39)(40)(41)(42). In non-human primates with LPS-induced lung inflammation, low-dose CO reduces BALF TNF-α and neutrophil levels (25). In studies with mice and human cells low-dose CO upregulated SPM levels by increasing lipoxygenase expression, the initiating enzymes for SPM biosynthesis, and inhibiting enzyme(s) involved in the further conversion of SPM.…”

“…CO gas upregulates the expression of 15-lipoxygenase type 1, a key enzyme in SPM biosynthesis, and prolongs SPM bioactivity by inhibiting inactivation (21). Moreover, inhaled CO has been shown to accelerate the resolution of acute inflammation in murine peritonitis (21,24) and in a nonhuman primate model of lung inflammation (25).…”

Carbon Monoxide Activates Autophagy via Mitochondrial Reactive Oxygen Species Formation

“…Although the clinical application of CO in humans for diseases of the lung remains unrealized, the feasibility of low-dose CO application in humans and nonhuman primates has now been tested (42)(43)(44). A recent study shows potential therapeutic effects of CO in human subjects with chronic obstructive pulmonary disease (44).…”

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

“…46 Similar, though less pronounced anti-inflammatory effects were observed in a non-human primate model of Cynomolgous macaques subjected to LPS challenge. 47 CO exposure following LPS inhalation decreased TNF-α release in broncoalveolar lavage (BAL) fluid, but had no apparent effect on IL-6 and IL-8 release, in addition to reducing pulmonary neutrophilia at the highest concentration (500 ppm). The therapeutic efficacy of CO in this model required relatively high doses that resulted in elevated carboxyhemoglobin (CO-Hb) levels (>30%).…”

“…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.…”