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Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia.

ABSTRACT: Adipose-derived stem cells (AdSCs) have recently been considered a useful treatment tool for autoimmune disease because of their anti-inflammatory and immunosuppressive effects. We investigated the therapeutic effect of intravenous AdSC transplantation in a mouse model of bleomycin-induced lung injury. AdSCs accumulated in the pulmonary interstitium and inhibited both inflammation and fibrosis in the lung, markedly improving the survival rate of mice with bleomycin-induced lung injury in a cell number-dependent manner. AdSCs inhibited the production of pro-inflammatory cytokines such as TNF-? and IL-12 in activated macrophages, and AdSCs also induced the apoptosis of activated macrophages. AdSCs inhibited the differentiation and proliferation of Th2-type mCD4+ T cells but promoted the differentiation and proliferation of regulatory T cells, suggesting that the phenotypic conversion of T cells may be one of the mechanisms for the anti-inflammatory effect of AdSCs on pulmonary fibrosis. These findings suggest that intravenous AdSCs could be a promising treatment for patients with interstitial pneumonia.

SUBMITTER: Kotani T

PROVIDER: S-EPMC5668313 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia.

Kotani Takuya T Masutani Ryota R Suzuka Takayasu T Oda Katsuhiro K Makino Shigeki S Ii Masaaki M

Scientific reports 20171106 1

Adipose-derived stem cells (AdSCs) have recently been considered a useful treatment tool for autoimmune disease because of their anti-inflammatory and immunosuppressive effects. We investigated the therapeutic effect of intravenous AdSC transplantation in a mouse model of bleomycin-induced lung injury. AdSCs accumulated in the pulmonary interstitium and inhibited both inflammation and fibrosis in the lung, markedly improving the survival rate of mice with bleomycin-induced lung injury in a cell ...[more]

PMID: 29097816

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Project description:BackgroundIdiopathic non-specific interstitial pneumonia (iNSIP), idiopathic pleuroparenchymal fibroelastosis (iPPFE), and unclassifiable idiopathic interstitial pneumonia (IIP) are IIPs with chronic fibrotic phenotypes, and unlike idiopathic pulmonary fibrosis, they have often been treated with anti-inflammatory drugs, including corticosteroids and immunosuppressants. However, the impact of bronchoalveolar lavage (BAL) lymphocytosis on the effects of anti-inflammatory therapy has never been evaluated. This study aimed to elucidate whether BAL lymphocytosis can be used to predict the efficacy of anti-inflammatory drugs for iNSIP, iPPFE, and unclassifiable IIP.MethodsJapanese patients diagnosed with iNSIP, iPPFE, and unclassifiable IIP by multidisciplinary discussion were identified using the nationwide registry. Eligible patients were stratified into four groups with and without BAL lymphocytosis and anti-inflammatory therapy to compare overall survival (OS) and changes in lung function. BAL lymphocytosis was defined as a lymphocyte differential count > 15%, and the cut-off was corroborated by survival classification and regression tree analysis.ResultsOverall, 186 patients (37 iNSIP, 16 iPPFE, and 133 unclassifiable IIP) were analyzed. Limited to patients treated with anti-inflammatory drugs (n = 123), patients with BAL lymphocytosis had a better prognosis [hazard ratio (HR), 0.26; 95% confidence interval (CI), 0.11-0.63; P = 0.003], higher slope of forced vital capacity (FVC) % predicted for 2 years, and longer OS (log-rank test, P = 0.012) than those without BAL lymphocytosis. On multivariate analysis, BAL lymphocytosis (HR 0.31; 95% CI 0.13-0.75; P = 0.009) was a prognostic factor for OS, along with age and FVC % predicted. Conversely, for patients managed without anti-inflammatory therapy (n = 63), the presence or absence of BAL lymphocytosis had no prognostic value.ConclusionsBAL lymphocytosis is associated with good outcomes in patients treated with anti-inflammatory drugs, but has no prognostic value when anti-inflammatory drugs are not used. BAL lymphocytosis may provide a predictive biomarker for identifying patients with iNSIP, iPPFE and unclassifiable IIP who are likely to benefit from anti-inflammatory drugs.

Project description:ObjectiveSecretoglobin (SCGB) 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM)-induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known.MethodsMice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods.ResultsBLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGFβ were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs.ConclusionThe role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2-null mice to BLM-induced pulmonary fibrosis.

Dataset Information

Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia.

Publications

Anti-inflammatory and anti-fibrotic effects of intravenous adipose-derived stem cell transplantation in a mouse model of bleomycin-induced interstitial pneumonia.

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