title: Lung Ischemia-Reperfusion is a Sterile Inflammatory Process Influenced by Commensal Microbiota in Mice.
abstract: 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 worsen acute lung injury. We previously reported that lung and systemic inflammation in a mouse model of ventilated lung IR depends on Toll-like receptor 4 (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. Lung IR was created in intubated mechanically ventilated mice via reversible left pulmonary artery occlusion followed by reperfusion. Inflammatory markers and histology were tracked during varying periods of reperfusion (from 1 to 24 h). Separate groups of mice were given intestinally localized antibiotics for 8 to 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, lipopolysaccharide and Pam3Cys. We found that inflammation generated by left lung IR was rapid in onset and dissipated within 12 to 24 h. Treatment of mice with intestinally localized antibiotics was associated with a marked attenuation of circulating and lung inflammatory markers as well as reduced histologic evidence of infiltrating cells and edema in the lung after IR. Alveolar macrophages from antibiotic-treated mice produced less cytokines ex vivo when stimulated with TLR agonists as compared with those from control mice. Our data indicate that the inflammatory response induced by nonhypoxic lung IR is transient and is strongly influenced by intestinal microbiota. Furthermore, these data suggest that the intestinal microbiome could potentially be manipulated to attenuate the post-IR pulmonary inflammatory response.
authors.affiliation: *Department of Anesthesia and Perioperative Care, University of California-San Francisco, San Francisco, California; †Otsuka America Pharmaceutical Inc, Princeton, New Jersey; ‡Department of Pulmonary Disease, Huadong Hospital, Fudan University, Shanghai, China; and §Department of Laboratory Medicine, and ∥Division of Critical Care Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Arun
authors.initials: A
authors.lastname: Prakash
authors.forename: Shirin V
authors.initials: SV
authors.lastname: Sundar
authors.forename: Ying-Gang
authors.initials: YG
authors.lastname: Zhu
authors.forename: Alphonso
authors.initials: A
authors.lastname: Tran
authors.forename: Jae-Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Clifford
authors.initials: C
authors.lastname: Lowell
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D058847:Inflammasomes / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D007422:Intestines / Q000382:microbiology; D008168:Lung / Q000098:blood supply*; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000502:physiology; D008297:Male; D008815:Mice, Inbred Strains; D064307:Microbiota / Q000187:drug effects / Q000502:physiology*; D020556:Neutrophil Infiltration; D011014:Pneumonia / Q000209:etiology / Q000382:microbiology* / Q000473:pathology / Q000517:prevention & control; D015427:Reperfusion Injury / Q000150:complications / Q000382:microbiology*; D013559:Symbiosis; D051195:Toll-Like Receptor 2 / Q000819:agonists; D051197:Toll-Like Receptor 4 / Q000819:agonists
chemical_list: D000900:Anti-Bacterial Agents; D018925:Chemokines; D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4