title: NFATc3 and VIP in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease.
abstract: Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both debilitating lung diseases which can lead to hypoxemia and pulmonary hypertension (PH). Nuclear Factor of Activated T-cells (NFAT) is a transcription factor implicated in the etiology of vascular remodeling in hypoxic PH. We have previously shown that mice lacking the ability to generate Vasoactive Intestinal Peptide (VIP) develop spontaneous PH, pulmonary arterial remodeling and lung inflammation. Inhibition of NFAT attenuated PH in these mice suggesting a connection between NFAT and VIP. To test the hypotheses that: 1) VIP inhibits NFAT isoform c3 (NFATc3) activity in pulmonary vascular smooth muscle cells; 2) lung NFATc3 activation is associated with disease severity in IPF and COPD patients, and 3) VIP and NFATc3 expression correlate in lung tissue from IPF and COPD patients. NFAT activity was determined in isolated pulmonary arteries from NFAT-luciferase reporter mice. The % of nuclei with NFAT nuclear accumulation was determined in primary human pulmonary artery smooth muscle cell (PASMC) cultures; in lung airway epithelia and smooth muscle and pulmonary endothelia and smooth muscle from IPF and COPD patients; and in PASMC from mouse lung sections by fluorescence microscopy. Both NFAT and VIP mRNA levels were measured in lungs from IPF and COPD patients. Empirical strategies applied to test hypotheses regarding VIP, NFATc3 expression and activity, and disease type and severity. This study shows a significant negative correlation between NFAT isoform c3 protein expression levels in PASMC, activity of NFATc3 in pulmonary endothelial cells, expression and activity of NFATc3 in bronchial epithelial cells and lung function in IPF patients, supporting the concept that NFATc3 is activated in the early stages of IPF. We further show that there is a significant positive correlation between NFATc3 mRNA expression and VIP RNA expression only in lungs from IPF patients. In addition, we found that VIP inhibits NFAT nuclear translocation in primary human pulmonary artery smooth muscle cells (PASMC). Early activation of NFATc3 in IPF patients may contribute to disease progression and the increase in VIP expression could be a protective compensatory mechanism.
authors.affiliation: Stony Brook University, Department of Technology and Society, College of Engineering and Applied Sciences, Stony Brook, NY, United States of America.|The Stony Brook Medicine SUNY at Stony Brook Internal Medicine Residency Program at John T. Mather Memorial Hospital, Port Jefferson, NY, United States of America.|Department of Occupational Medicine, Epidemiology, and Preventive Medicine, Hofstra Northwell School of Medicine at Hofstra University, Hempstead and Manhasset, NY, United States of America.|Three Village Allergy & Asthma, PLLC, South Setauket, NY, United States of America.|Columbia University Child Psychiatric Epidemiology Group, New York, NY, United States of America.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Szema
authors.affiliation: Stony Brook University School of Medicine M.D. with Scholarly Recognition Program, Stony Brook, NY, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Forsyth
authors.affiliation: Stony Brook University School of Medicine M.D. with Scholarly Recognition Program, Stony Brook, NY, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ying
authors.affiliation: Department of Internal Medicine, Bronx Veterans Affairs Medical Center Internal Medicine Residency Program, Bronx, NY, United States of America.
authors.forename: Sayyed A
authors.initials: SA
authors.lastname: Hamidi
authors.affiliation: Biostatistics and Data Management Core, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Pathology, SUNY Stony Brook School of Medicine, Stony Brook, NY, United States of America.
authors.forename: Sonya
authors.initials: S
authors.lastname: Hwang
authors.affiliation: Three Village Allergy & Asthma, PLLC, South Setauket, NY, United States of America.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Li
authors.affiliation: Stony Brook University, Department of Technology and Society, College of Engineering and Applied Sciences, Stony Brook, NY, United States of America.
authors.forename: Debra
authors.initials: D
authors.lastname: Sabatini Dwyer
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Ramiro-Diaz
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America.
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Giermakowska
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Gonzalez Bosc
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D054990:Idiopathic Pulmonary Fibrosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014660:Vasoactive Intestinal Peptide / Q000235:genetics* / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; D014660:Vasoactive Intestinal Peptide