Lung Ischemia-Reperfusion is a Sterile Inflammatory Process Influenced by Commensal Microbiota in Mice

Abstract

Background Lung ischemia reperfusion (IR) complicates numerous clinical processes, such as cardiac arrest, transplantation, and major trauma. These conditions generate sterile inflammation, which can cause or augment acute lung injury. We previously reported that lung and systemic inflammation in a mouse model of ventilated lung IR depends on Toll-like receptor (TLR) 4 signaling and the presence of alveolar macrophages. Here, we tested the hypothesis that the intestinal microbiome has a role in influencing the inflammatory response to lung IR. Methods Lung IR was created in intubated mechanically ventilated mice via reversible left pulmonary artery occlusion followed by reperfusion. Inflammatory markers and histology were tracked over varying periods of reperfusion (from 1h to 24h). Separate groups of mice were given intestinally-localized antibiotics for 8-10 weeks, and then were subjected to left lung IR and analysis of lungs and plasma for markers of inflammation. Alveolar macrophages from antibiotic-treated or control mice were tested ex vivo for inflammatory responses to bacterial TLR agonists, namely LPS and Pam3Cys. Results Inflammation generated by left lung IR was rapid in onset and dissipated within 12-24h. Treatment of mice with intestinally localized antibiotics was associated with a marked attenuation of circulating and lung inflammatory markers, and histologic evidence of infiltrating cells and edema in the lung following IR. Alveolar macrophages from antibiotic-treated mice produced less cytokines ex vivo when stimulated with TLR agonists as compared to those from control mice. Conclusions Our data indicate that the inflammatory response induced by lung IR is transient and is strongly influenced by intestinal microbiota. These data suggest that the intestinal microbiome could potentially be manipulated to attenuate the post-IR pulmonary inflammatory response.

Ischemia/Reperfusion

“…In support of this concept, depletion of gut commensal bacteria by antibiotic treatment was reported to be effective in reducing intestinal mucosal and lung injury induced by bowel ischemia (733, 890). Interestingly, antibiotic depletion of the intestinal microbiome also reduced infarct size after myocardial I/R and stroke (63, 466, 640, 733, 830, 890), which is discussed in greater detail later.…”

Mechanisms of lung ischemia-reperfusion injury

“…Finally, although IR injury is considered a sterile inflammatory condition, an interesting study by Prakash et al . suggests that the inflammatory response induced by lung IR is transient and strongly influenced by intestinal microbiota [20]. Here, treatment of mice with intestinally localized antibiotics was associated with attenuation of lung inflammatory markers, cell infiltration and edema in the lung after IR.…”

Collapse of the Microbiome, Emergence of the Pathobiome, and the Immunopathology of Sepsis

“…Pseudomonas will eventually colonize the gut following lung inoculation and can express a wide variety of antibiotics that normally kill off competing bacteria, thus dramatically altering the microbiome (27). The microbiome itself plays a key role in regulating the local, lung and systemic immune system (28, 29). Fecal transplants are able to rescue mice from lethal pneumonias and patients routinely receive broad spectrum antibiotics when being treated for pneumonia which will necessarily alter the gut microbiota (30).…”