Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury
| Autor: | Xin Xu, Amit Gaggar, Shi Wei, Hongwei Qin, Jiping Zhao, Sara A. Gibson, Chenglong Li, Hao Yu, Etty N. Benveniste, Yudong Liu, Pui-Kai Li, Zhaoqi Yan |
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| Rok vydání: | 2016 |
| Předmět: |
Lipopolysaccharides
STAT3 Transcription Factor 0301 basic medicine Pulmonary and Respiratory Medicine ARDS Physiology Acute Lung Injury Anthraquinones Cell Separation Acute respiratory distress Lung injury 03 medical and health sciences 0302 clinical medicine Physiology (medical) Animals Humans Medicine Myeloid Cells STAT3 Inflammation Respiratory Distress Syndrome Sulfonamides Integrases biology business.industry Macrophages High mortality JAK-STAT signaling pathway Pneumonia Cell Biology respiratory system medicine.disease respiratory tract diseases Mice Inbred C57BL Disease Models Animal 030104 developmental biology Gene Expression Regulation Suppressor of Cytokine Signaling 3 Protein 030220 oncology & carcinogenesis Immunology Call for Papers Leukocytes Mononuclear biology.protein Chemokines Inflammation Mediators business Bronchoalveolar Lavage Fluid Gene Deletion |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 311:L868-L880 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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/fl mice 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. |
| Databáze: | OpenAIRE |
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