Abstract
Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. In this study, the bleomycin experimental model of pulmonary fibrosis was employed to investigate the anti-fibrotic and immunomodulatory activity of the inhibition of MALT1 protease activity. Mice received a single intra-tracheal administration of bleomycin (1 mg/kg) in the presence or absence of MI-2, a selective MALT1 inhibitor, (a dose of 30 mg/kg administered intra-peritoneally 1 h after bleomycin and daily until the end of the experiment). Seven days after bleomycin instillation mice were sacrificed and bronchoalveolar lavage fluid analysis, measurement of collagen content in the lung, histology, molecular analysis and immunohistochemistry were performed. To evaluate mortality and body weight gain a subset of mice was administered daily with MI-2 for 21 days. Mice that received MI-2 showed decreased weight loss and mortality, inflammatory cells infiltration, cytokines overexpression and tissue injury. Moreover, biochemical and immunohistochemical analysis displayed that MI-2 was able to modulate the excessive production of reactive oxygen species and the inflammatory mediator upregulation induced by bleomycin instillation. Additionally, MI-2 demonstrated anti-fibrotic activity by reducing transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA) and receptor associated factor 6 (TRAF6) expression. The underlying mechanisms for the protective effect of MI-2 bleomycin induced pulmonary fibrosis may be attributed to its inhibition on NF-κB pathway. This is the first report showing the therapeutic role of MALT1 inhibition in a bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.
Highlights
Persistent airway stimulation from nonantigenic and antigenic sources leads to pulmonary fibrosis, producing progressive remodeling of lung architecture by deposition of collagen [1,2,3]
Many mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) substrates are implicated in the regulation of the inflammatory answers, its protease activity is emerging as therapeutic tool [9,10]
Seven days after bleomycin administration, histological analysis of lung samples harvested from vehicle-treated mice showed tissue injury and extracellular matrix deposition (Figure 1B,E), as compared to sham animals (Figure 1A,E)
Summary
Persistent airway stimulation from nonantigenic and antigenic sources leads to pulmonary fibrosis, producing progressive remodeling of lung architecture by deposition of collagen [1,2,3]. Thanks to its pulmonary toxicity, administration of bleomycin is a widely used model of pulmonary fibrosis. This model is characterized by increased inflammatory cell response, collagen deposition and T lymphocyte activation. Seven days after bleomycin-induced injury inflammation is accompanied with fibroproliferative activity. It modifies the antioxidant/oxidant balance and increased lipid peroxidation. Many MALT1 substrates are implicated in the regulation of the inflammatory answers, its protease activity is emerging as therapeutic tool [9,10]
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