Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Inhibitor as a Novel Therapeutic Tool for Lung Injury.

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.

• Authors: Roberta Fusco, Rosalba Siracusa, Ramona D'Amico, Marika Cordaro, Tiziana Genovese, Enrico Gugliandolo, Alessio Filippo Peritore, Rosalia Crupi, Rosanna Di Paola, Salvatore Cuzzocrea, Daniela Impellizzeri
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 20 (Oct 20 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33092214 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Enzyme Inhibitors
• NF-kappa B
• TNF Receptor-Associated Factor 6
• Transforming Growth Factor beta
• Bleomycin
• Collagen
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Topics

• Animals
• Bleomycin
• Bronchoalveolar Lavage Fluid (chemistry)
• Collagen (metabolism)
• Cytokines (metabolism)
• Enzyme Inhibitors (pharmacology)
• Lung (drug effects, metabolism, pathology)
• Lung Injury (metabolism, prevention & control)
• Male
• Mice
• Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein (antagonists & inhibitors, metabolism)
• NF-kappa B (metabolism)
• Pulmonary Fibrosis (chemically induced, drug therapy, metabolism)
• Signal Transduction (drug effects)
• TNF Receptor-Associated Factor 6 (metabolism)
• Transforming Growth Factor beta (metabolism)