title: Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury.
abstract: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are diseases with high mortality. Macrophages and neutrophils are responsible for inflammatory responses in ALI and ARDS, which are characterized by excessive production of proinflammatory mediators in bronchoalveolar lavage fluid (BALF) and plasma. Aberrant activation of the JAK/STAT pathway is critical for persistent inflammation in many conditions such as infection and autoimmunity. Given the importance of the STAT3 transcription factor in activating macrophages and neutrophils and augmenting inflammation, we investigated the therapeutic potential of inhibiting STAT3 activity using the small-molecule STAT3 inhibitor, LLL12. Our results demonstrate that LPS induces STAT3 activation in macrophages in vitro and in CD45+CD11b+cells from BALF in the LPS-induced ALI model in vivo. LLL12 treatment inhibits LPS-induced lung inflammation in the ALI model, which is accompanied by suppression of LPS-induced STAT3 activation and an inhibition of macrophage and inflammatory cell infiltration in lung and BALF. LLL12 treatment also suppresses expression of proinflammatory genes including IL-1β, IL-6, TNF-α, iNOS, CCL2, and MHC class II in macrophages and inflammatory cells from BALF and serum as determined by ELISA. Furthermore, hyperactivation of STAT3 in LysMCre-SOCS3fl/flmice accelerates the severity of inflammation in the ALI model. Both pre- and post-LPS treatment with LLL12 decrease LPS-induced inflammatory responses in mice with ALI. Importantly, LLL12 treatment attenuates STAT3 phosphorylation in human peripheral blood mononuclear cells induced by plasma from patients with ARDS, which suggests the feasibility of targeting the STAT3 pathway therapeutically for patients with ALI and ARDS.
authors.affiliation: Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.|Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Jiping
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Gibson
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Zhaoqi
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.|Birmingham VA Medical Center, University of Alabama at Birmingham, Birmingham, Alabama.|Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.|Birmingham VA Medical Center, University of Alabama at Birmingham, Birmingham, Alabama.|Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio.
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; hqin@uab.edu.
authors.forename: Hongwei
authors.identifier: 0000-0002-7511-5078
authors.initials: H
authors.lastname: Qin
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000097:blood; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D018925:Chemokines; D018836:Inflammation Mediators; C549232:LLL12 compound; D008070:Lipopolysaccharides; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D013449:Sulfonamides; D000071223:Suppressor of Cytokine Signaling 3 Protein; C045073:Cre recombinase; D019426:Integrases
keywords: JAK/STAT pathway; acute lung injury; suppressor of cytokine signaling-3, STAT3 inhibitor