title: Interleukin 13- and interleukin 17A-induced pulmonary hypertension phenotype due to inhalation of antigen and fine particles from air pollution.
abstract: Pulmonary hypertension has a marked detrimental effect on quality of life and life expectancy. In a mouse model of antigen-induced pulmonary arterial remodeling, we have recently shown that coexposure to urban ambient particulate matter (PM) significantly increased the thickening of the pulmonary arteries and also resulted in significantly increased right ventricular systolic pressures. Here we interrogate the mechanism and show that combined neutralization of interleukin 13 (IL-13) and IL-17A significantly ameliorated the increase in right ventricular systolic pressure, the circumferential muscularization of pulmonary arteries, and the molecular change in the right ventricle. Surprisingly, our data revealed a protective role of IL-17A for the antigen- and PM-induced severe thickening of pulmonary arteries. This protection was due to the inhibition of the effects of IL-13, which drove this response, and the expression of metalloelastase and resistin-like molecule α. However, the latter was redundant for the arterial thickening response. Anti-IL-13 exacerbated airway neutrophilia, which was due to a resulting excess effect of IL-17A, confirming concurrent cross inhibition of IL-13- and IL-17A-dependent responses in the lungs of animals exposed to antigen and PM. Our experiments also identified IL-13/IL-17A-independent molecular reprogramming in the lungs induced by exposure to antigen and PM, which indicates a risk for arterial remodeling and protection from arterial constriction. Our study points to IL-13- and IL-17A-coinduced inflammation as a new template for biomarkers and therapeutic targeting for the management of immune response-induced pulmonary hypertension.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.
authors.forename: Sung-Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA ; Current affiliation: Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
authors.forename: Nafiseh
authors.initials: N
authors.lastname: Esmaeil
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lucas
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
authors.forename: Leigh M
authors.initials: LM
authors.lastname: Marsh
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA ; Pulmonary Medicine, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Reibman
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA ; Pulmonary Medicine, Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Grunig
keywords: air pollution; inhaled antigen; particulate matter 2.5; pulmonary vasculature