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Protective Effects of Anti-IL17 on Acute Lung Injury Induced by LPS in Mice.

ABSTRACT: Introduction: T helper 17 (Th17) has been implicated in a variety of inflammatory lung and immune system diseases. However, little is known about the expression and biological role of IL-17 in acute lung injury (ALI). We investigated the mechanisms involved in the effect of anti-IL17 in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Methods: Mice were pre-treated with anti-IL17, 1h before saline/LPS intratracheal administration alongside non-treated controls and levels of exhaled nitric oxide (eNO), cytokine expression, extracellular matrix remodeling and oxidative stress, as well as immune cell counts in bronchoalveolar lavage fluid (BALF), and respiratory mechanics were assessed in lung tissue. Results: LPS instillation led to an increase in multiple cytokines, proteases, nuclear factor-?B, and Forkhead box P3 (FOXP3), eNO and regulators of the actomyosin cytoskeleton, the number of CD4+ and iNOS-positive cells as well as the number of neutrophils and macrophages in BALF, resistance and elastance of the respiratory system, ARG-1 gene expression, collagen fibers, and actin and 8-iso-PGF2? volume fractions. Pre-treatment with anti-IL17 led to a significant reduction in the level of all assessed factors. Conclusions: Anti-IL17 can protect the lungs from the inflammatory effects of LPS-induced ALI, primarily mediated by the reduced expression of cytokines and oxidative stress. This suggests that further studies using anti-IL17 in a treatment regime would be highly worthwhile.

SUBMITTER: Righetti RF

PROVIDER: S-EPMC6180195 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Protective Effects of Anti-IL17 on Acute Lung Injury Induced by LPS in Mice.

Righetti Renato Fraga RF Dos Santos Tabata Maruyama TM Camargo Leandro do Nascimento LDN Aristóteles Luciana Ritha Cássia Rolim Barbosa LRCRB Fukuzaki Silvia S de Souza Flávia Castro Ribas FCR Santana Fernanda Paula Roncon FPR de Agrela Marcus Vinicius Rodrigues MVR Cruz Maysa Mariana MM Alonso-Vale Maria Isabel Cardoso MIC Genaro Isabella Santos IS Saraiva-Romanholo Beatriz Mangueira BM Leick Edna Aparecida EA Martins Milton de Arruda MA Prado Carla Máximo CM Tibério Iolanda de Fátima Lopes Calvo IFLC

Frontiers in pharmacology 20181004

<b>Introduction:</b> T helper 17 (Th17) has been implicated in a variety of inflammatory lung and immune system diseases. However, little is known about the expression and biological role of IL-17 in acute lung injury (ALI). We investigated the mechanisms involved in the effect of anti-IL17 in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. <b>Methods:</b> Mice were pre-treated with anti-IL17, 1h before saline/LPS intratracheal administration alongside non-treated co ...[more]

PMID: 30337870

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Project description:BackgroundAcute 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.MethodsUsing 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.ResultsWe 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.ConclusionTogether 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.

Project description:Bletilla striata is a well-known traditional Chinese herb with anti-inflammatory properties that is widely used in the treatment of lung conditions such as silicosis, tuberculosis, and pneumogastric hemorrhage. However, little information on the anti-inflammatory ingredients and their activities is available. In this study, an effect fraction of Bletilla striata (EFBS) was enriched, and its anti-inflammatory activities and underlying mechanisms were investigated. EFBS was enriched by polyamide column chromatography and characterized by HPLC; an LPS-induced acute lung injury model was used to evaluate the anti-inflammatory activities of EFBS. Meanwhile, the main anti-inflammation-contributing ingredients and possible molecular mechanism of anti-inflammatory activity in EFBS were verified by component-knockout method combined with LPS-induced RAW264.7 cell model. The EFBS mainly consisted of coelonin (15.88%), batatasin III (32.49%), 3'-O-methylbatatasin III (6.96%), and 3-hydroxy-5-methoxy bibenzyl (2.51%). Pretreatment with the EFBS (20 mg/kg and 60 mg/kg) for five days prior to the administration of LPS resulted in decreases in wet-to-dry lung weight ratio, neutrophil number, MPO activity, total protein concentration, NO level, and MDA level, as well as IL-1β, IL-6, MCP-1, and TNF-α concentrations in the bronchoalveolar lavage fluid. Western blot analysis demonstrated the increased expressions of iNOS, COX-2, and NF-κB p65 in the LPS treatment group, all of which were ameliorated by EFBS pretreatment. Histological examination confirmed the protective effect of the EFBS. Additionally, component-knockout assay confirmed that these four quantitative components contributed significantly to the anti-inflammatory effect of EFBS. Coelonin, batatasin III, 3'-O-methylbatatasin III and 3-hydroxy-5-methoxy bibenzyl were the main anti-inflammatory components of EFBS and could regulate the expression of downstream inflammatory cytokines by inhibiting p65 nuclear translocation. These findings uncover, in part, the molecular basis underlying the anti-inflammatory activity of Bletilla striata.

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Protective Effects of Anti-IL17 on Acute Lung Injury Induced by LPS in Mice.

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Protective Effects of Anti-IL17 on Acute Lung Injury Induced by LPS in Mice.

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