Please use this identifier to cite or link to this item: https://doi.org/10.1186/s10020-022-00500-w
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dc.titleISM1 suppresses LPS-induced acute lung injury and post-injury lung fibrosis in mice
dc.contributor.authorNguyen, Ngan
dc.contributor.authorXu, Simin
dc.contributor.authorLam, Terence Yin Weng
dc.contributor.authorLiao, Wupeng
dc.contributor.authorWong, WS Fred
dc.contributor.authorGe, Ruowen
dc.date.accessioned2022-07-20T09:47:12Z
dc.date.available2022-07-20T09:47:12Z
dc.date.issued2022-12-01
dc.identifier.citationNguyen, Ngan, Xu, Simin, Lam, Terence Yin Weng, Liao, Wupeng, Wong, WS Fred, Ge, Ruowen (2022-12-01). ISM1 suppresses LPS-induced acute lung injury and post-injury lung fibrosis in mice. MOLECULAR MEDICINE 28 (1). ScholarBank@NUS Repository. https://doi.org/10.1186/s10020-022-00500-w
dc.identifier.issn10761551
dc.identifier.issn15283658
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/228956
dc.description.abstractBackground: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear. Methods: Using Ism1-/- mice and intratracheal LPS-induced ALI, and local delivery of recombinant ISM1 (rISM1), we investigated the role ISM1 plays in ALI and post-ALI lung fibrosis using flow cytometry, Western blot, antibody array, immunohistochemistry (IHC), immunofluorescent and other histological staining. Results: We reveal that ISM1 deficiency in mice led to an intensified acute lung inflammation upon intratracheal LPS challenge, with a heightened leukocyte infiltration including neutrophils and monocyte-derived alveolar macrophages, as well as upregulation of multiple pro-inflammatory cytokines/chemokines including tumor necrosis factor α (TNF-α). Although innate immune cells largely subsided to the baseline by day 7 post-LPS challenge in both wild-type and Ism1−/− mice, Ism1−/− lung showed increased post-ALI fibrosis from day 9 post-LPS treatment with increased myofibroblasts, excessive collagen accumulation and TGF-β upregulation. The heightened lung fibrosis remained on day 28 post-LPS. Moreover, intranasal delivered recombinant ISM1 (rISM1) effectively suppressed LPS-induced acute lung inflammation and ALI, and rISM1 suppressed LPS-induced NF-κB activation in cultured mouse alveolar macrophages. Conclusion: Together with our previous report, this work further established ISM1 as an endogenous anti-inflammation protein in the lung, restraining excessive host inflammatory response to LPS-triggered ALI and suppressing post-ALI lung fibrosis likely through suppressing NF-κB activation and pro-inflammatory cytokine/chemokine production.
dc.language.isoen
dc.publisherSPRINGER
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectBiochemistry & Molecular Biology
dc.subjectCell Biology
dc.subjectMedicine, Research & Experimental
dc.subjectResearch & Experimental Medicine
dc.subjectISM1
dc.subjectLPS
dc.subjectInflammation
dc.subjectAcute lung injury
dc.subjectPulmonary fibrosis
dc.subjectRESPIRATORY-DISTRESS-SYNDROME
dc.subjectKAPPA-B
dc.subjectINFLAMMATORY RESPONSES
dc.subjectISTHMIN
dc.subjectTHROMBOSPONDIN-1
dc.subjectANGIOSTATIN
dc.subjectINHIBITION
dc.subjectRESOLUTION
dc.subjectAPOPTOSIS
dc.subjectENDOTOXIN
dc.typeArticle
dc.date.updated2022-07-17T03:34:03Z
dc.contributor.departmentDEPT OF BIOLOGICAL SCIENCES
dc.contributor.departmentDEPT OF PHARMACOLOGY
dc.description.doi10.1186/s10020-022-00500-w
dc.description.sourcetitleMOLECULAR MEDICINE
dc.description.volume28
dc.description.issue1
dc.published.stateUnpublished
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