title: Age-Dependent Susceptibility to Pulmonary Fibrosis Is Associated with NLRP3 Inflammasome Activation.
abstract: Aging has been implicated in the development of pulmonary fibrosis, which has seen a sharp increase in incidence in those older than 50 years. Recent studies demonstrate a role for the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome and its regulated cytokines in experimental lung fibrosis. In this study, we tested the hypothesis that age-related NLRP3 inflammasome activation is an important predisposing factor in the development of pulmonary fibrosis. Briefly, young and aged wild-type and NLRP3(-/-) mice were subjected to bleomycin-induced lung injury. Pulmonary fibrosis was determined by histology and hydroxyproline accumulation. Bone marrow and alveolar macrophages were isolated from these mice. NLRP3 inflammasome activation was assessed by co-immunoprecipitation experiments. IL-1β and IL-18 production was measured by ELISA. The current study demonstrated that aged wild-type mice developed more lung fibrosis and exhibited increased morbidity and mortality after bleomycin-induced lung injury, when compared with young mice. Bleomycin-exposed aged NLRP3(-/-) mice had reduced fibrosis compared with their wild-type age-matched counterparts. Bone marrow-derived and alveolar macrophages from aged mice displayed higher levels of NLRP3 inflammasome activation and caspase-1-dependent IL-1β and IL-18 production, which was associated with altered mitochondrial function and increased production of reactive oxygen species. Our study demonstrated that age-dependent increases in alveolar macrophage mitochondrial reactive oxygen species production and NLRP3 inflammasome activation contribute to the development of experimental fibrosis.
authors.affiliation: 1 Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medical College, New York, New York.|2 Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and.
authors.forename: Heather W
authors.initials: HW
authors.lastname: Stout-Delgado
authors.affiliation: 1 Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: 3 Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Chu
authors.affiliation: 2 Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and.
authors.forename: Dana N
authors.initials: DN
authors.lastname: Mitzel
authors.affiliation: 2 Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and.|3 Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Julian
authors.initials: J
authors.lastname: Villalba
authors.affiliation: 2 Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and.|3 Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Souheil
authors.initials: S
authors.lastname: El-Chemaly
authors.affiliation: 1 Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medical College, New York, New York.|3 Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: 1 Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medical College, New York, New York.|3 Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: 2 Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and.|3 Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ivan O
authors.identifier: 0000-0003-4622-618X
authors.initials: IO
authors.lastname: Rosas
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001761:Bleomycin; D004198:Disease Susceptibility; D058847:Inflammasomes / Q000378:metabolism*; D007322:Instillation, Drug; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000150:complications / Q000473:pathology / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000172:deficiency / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000150:complications / Q000473:pathology* / Q000517:prevention & control; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016212:Transforming Growth Factor beta; D001761:Bleomycin
keywords: NLRP3 inflammasome; aging; bleomycin; mitochondrial oxidative stress; pulmonary fibrosis