title: Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming.
abstract: Despite intense investigation, acute respiratory distress syndrome (ARDS) remains an enormous clinical problem for which no specific therapies currently exist. In this study, we used intratracheal lipopolysaccharide or Pseudomonas bacteria administration to model experimental acute lung injury (ALI) and to further understand mediators of the resolution phase of ARDS. Recent work demonstrates macrophages transition from a predominant proinflammatory M1 phenotype during acute inflammation to an anti-inflammatory M2 phenotype with ALI resolution. We tested the hypothesis that IL-4, a potent inducer of M2-specific protein expression, would accelerate ALI resolution and lung repair through reprogramming of endogenous inflammatory macrophages. In fact, IL-4 treatment was found to offer dramatic benefits following delayed administration to mice subjected to experimental ALI, including increased survival, accelerated resolution of lung injury, and improved lung function. Expression of the M2 proteins Arg1, FIZZ1, and Ym1 was increased in lung tissues following IL-4 treatment, and among macrophages, FIZZ1 was most prominently upregulated in the interstitial subpopulation. A similar trend was observed for the expression of macrophage mannose receptor (MMR) and Dectin-1 on the surface of alveolar macrophages following IL-4 administration. Macrophage depletion or STAT6 deficiency abrogated the therapeutic effect of IL-4. Collectively, these data demonstrate that IL-4-mediated therapeutic macrophage reprogramming can accelerate resolution and lung repair despite delayed use following experimental ALI. IL-4 or other therapies that target late-phase, proresolution pathways may hold promise for the treatment of human ARDS.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: F R
authors.initials: FR
authors.lastname: D'Alessio
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
authors.forename: J M
authors.initials: JM
authors.lastname: Craig
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: B D
authors.identifier: 0000-0001-5775-8427
authors.initials: BD
authors.lastname: Singer
authors.affiliation: Division of Pulmonary and Critical Care, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and.
authors.forename: D C
authors.identifier: 0000-0002-1595-4080
authors.initials: DC
authors.lastname: Files
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: J R
authors.initials: JR
authors.lastname: Mock
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: B T
authors.initials: BT
authors.lastname: Garibaldi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: J
authors.initials: J
authors.lastname: Fallica
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: A
authors.initials: A
authors.lastname: Tripathi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: P
authors.initials: P
authors.lastname: Mandke
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: J H
authors.initials: JH
authors.lastname: Gans
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
authors.forename: N
authors.initials: N
authors.lastname: Limjunyawong
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: V K
authors.initials: VK
authors.lastname: Sidhaye
authors.affiliation: Department of Anesthesiology and Critical Care, Johns Hopkins University, Baltimore, Maryland.
authors.forename: N M
authors.initials: NM
authors.lastname: Heller
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
authors.forename: W
authors.initials: W
authors.lastname: Mitzner
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: L S
authors.initials: LS
authors.lastname: King
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; naggarw1@jhmi.edu.
authors.forename: N R
authors.initials: NR
authors.lastname: Aggarwal
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D015847:Interleukin-4 / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000502:physiology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D015847:Interleukin-4
keywords: ARDS; acute lung injury; interleukin-4; macrophage; resolution