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Effect of Mycophenolate in a Mouse Model of Lung Fibrosis
Diffuse Lung Disease SESSION TITLE: Diffuse Lung Disease I SESSION TYPE: Original Investigation Slide PRESENTED ON: Sunday, October 29, 2017 at 03:15 PM - 04:15 PM
Effect of Mycophenolate in a Mouse Model of Lung Fibrosis Jose Castaneda* Claude Lesaux Cheresa Calhoun and Jay Peters University of Texas Health Science Center at San Antonio, San Antonio, TX PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease with a high mortality rate. Unfortunately, physicians have limited pharmacologic therapies that have been approve for the management of IPF. Nintedanib (Nb) is a tyrosine kinase inhibitor that reduces disease progression but may be associated with significant side effects and substantial financial cost. Mycophenolate mofetil (MMF) is a widely used potent immunosuppressive agent with important antiproliferative and antifibrotic properties. Recent studies demonstrate MMF has significant clinical benefit in patients with scleroderma (another pulmonary fibrotic disorder). We hypnotizes that MMF might be beneficial in patient with IPF and tested this hypothesis by comparing MMF to Nb using a mouse model of lung fibrosis. METHODS: Animal experimentation was conducted in accordance with international guidelines and regulations and approved by our institutional IACUC. Lung fibrosis was induced in mice by intratracheal injection with 2.5U/kg of Bleomycin. Three mice were given intratracheal PBS as a control group. All procedures were performed under anesthesia with the use of ketamine and xylazine. At day ten, the mice where randomize into three groups: Group A did not received further intervention; Group B received 100 mg/kg/ day of intraperitoneal MMF and Group C received 60 mg/kg /day of oral Nb. At day twenty-one, lung functions were measure with the use of a flexivent, then the mice where scarified. Bronchoalveolar lavage was performed and lung tissue was obtained for analysis (SIRCOL; PSR; qPCR on col1a2, p16, p21, IL-6, TGF-b; and pSmad2/3)
CONCLUSIONS: Data from this experiment suggests that MMF reduces collagen content and the burden of senescence via the P16 mRNA pathway. In a bleomycin model of lung fibrosis, we did not detect any significant difference in the antifibrotic properties between mycophenolate and nintedanib. CLINICAL IMPLICATIONS: MMF may have a therapeutic benefit, either alone or in combination with other agents, in the treatment of patients with IPF. Further studies are required to test this hypothesis. DISCLOSURE: The following authors have nothing to disclose: Jose Castaneda, Claude Lesaux, Cheresa Calhoun, Jay Peters No Product/Research Disclosure Information DOI:
http://dx.doi.org/10.1016/j.chest.2017.08.516
Copyright ª 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
chestjournal.org
489A
DIFFUSE LUNG DISEASE
RESULTS: The percentage of collagen in the parenchyma was reduced equally in the MMF and Nb groups (Group A/Bleo = 60%, Group B/MMF = 50%, Group C/Nb = 50 %.) Similarly, collagen mRNA was similarly reduced in the MMF and Nb groups (Col1a2 mRNA expression: Group A/Bleo = 2.35, Group B/MMF = 1.5, Group C/Nb = 1.5). Senescence was reduced via P16 mRNA pathway by both MMF and Nb (p16 mRNA relative expression: Group A/Bleo = 2.0, Group B/MMF = 0.8, Group C/Nb = 1.0)
Effect of Mycophenolate in a Mouse Model of Lung Fibrosis Jose Castaneda* Claude Lesaux Cheresa Calhoun and Jay Peters University of Texas Health Science Center at San Antonio, San Antonio, TX PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease with a high mortality rate. Unfortunately, physicians have limited pharmacologic therapies that have been approve for the management of IPF. Nintedanib (Nb) is a tyrosine kinase inhibitor that reduces disease progression but may be associated with significant side effects and substantial financial cost. Mycophenolate mofetil (MMF) is a widely used potent immunosuppressive agent with important antiproliferative and antifibrotic properties. Recent studies demonstrate MMF has significant clinical benefit in patients with scleroderma (another pulmonary fibrotic disorder). We hypnotizes that MMF might be beneficial in patient with IPF and tested this hypothesis by comparing MMF to Nb using a mouse model of lung fibrosis. METHODS: Animal experimentation was conducted in accordance with international guidelines and regulations and approved by our institutional IACUC. Lung fibrosis was induced in mice by intratracheal injection with 2.5U/kg of Bleomycin. Three mice were given intratracheal PBS as a control group. All procedures were performed under anesthesia with the use of ketamine and xylazine. At day ten, the mice where randomize into three groups: Group A did not received further intervention; Group B received 100 mg/kg/ day of intraperitoneal MMF and Group C received 60 mg/kg /day of oral Nb. At day twenty-one, lung functions were measure with the use of a flexivent, then the mice where scarified. Bronchoalveolar lavage was performed and lung tissue was obtained for analysis (SIRCOL; PSR; qPCR on col1a2, p16, p21, IL-6, TGF-b; and pSmad2/3)
CONCLUSIONS: Data from this experiment suggests that MMF reduces collagen content and the burden of senescence via the P16 mRNA pathway. In a bleomycin model of lung fibrosis, we did not detect any significant difference in the antifibrotic properties between mycophenolate and nintedanib. CLINICAL IMPLICATIONS: MMF may have a therapeutic benefit, either alone or in combination with other agents, in the treatment of patients with IPF. Further studies are required to test this hypothesis. DISCLOSURE: The following authors have nothing to disclose: Jose Castaneda, Claude Lesaux, Cheresa Calhoun, Jay Peters No Product/Research Disclosure Information DOI:
http://dx.doi.org/10.1016/j.chest.2017.08.516
Copyright ª 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
chestjournal.org
489A
DIFFUSE LUNG DISEASE
RESULTS: The percentage of collagen in the parenchyma was reduced equally in the MMF and Nb groups (Group A/Bleo = 60%, Group B/MMF = 50%, Group C/Nb = 50 %.) Similarly, collagen mRNA was similarly reduced in the MMF and Nb groups (Col1a2 mRNA expression: Group A/Bleo = 2.35, Group B/MMF = 1.5, Group C/Nb = 1.5). Senescence was reduced via P16 mRNA pathway by both MMF and Nb (p16 mRNA relative expression: Group A/Bleo = 2.0, Group B/MMF = 0.8, Group C/Nb = 1.0)