Impairment of the NKT–STAT1–CXCL9 Axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Caused by Lung Fibrosis

• DOI: 10.1164/rccm.202201-0142oc
• Publication Date: 2022-06-28T20:17:56Z
• Authors: Katharina Jandl; Leigh M. Marsh; Ayse Ceren Mutgan; Slaven Crnkovic; Francesco Valzano; Diana Zabini; Julia Hoffmann; Vasile Foris; Elisabeth Gschwan...; Walter Klepetko; Helmut Prosch; Holger Flick; Luka Brcic; Izidor Kern; Akos Heinemann; Horst Olschewski; Gabor Kovacs; Grazyna Kwapiszewska
• Keywords: CXCR3; Ex vivo

Rationale: Pulmonary hypertension (PH) is a common, severe comorbidity in interstitial lung diseases such as pulmonary fibrosis (PF), and it has limited treatment options. Excessive vascular inflammation are often present PH, but the underlying mechanisms still not well understood. Objectives: To identify novel functional link between natural killer T (NKT) cell activation PF-PH. Methods: Multicolor flow cytometry, secretome, immunohistological analyses were complemented by pharmacological NKT vivo, vitro, ex vivo. Measurements Main Results: In vessels of patients with PF-PH, increased collagen deposition was linked to local deficiency decreased IL-15 concentrations. mouse model PH caused fibrosis, using synthetic α-galactosylceramide analog (KRN7000) restored numbers ameliorated remodeling right ventricular systolic pressure. Supplementation activated cells reduced isolated human arterial smooth muscle (hPASMCs) vivo precision-cut slices end-stage Coculture induced STAT1 signaling hPASMCs. Secretome analysis peripheral blood mononuclear identified CXCL9 CXCL10 indicators activation. Pharmacologically, CXCL9, CXCL10, potently inhibited hPASMCs via chemokine receptor CXCR3. Conclusions: Our results indicate that absence impairs STAT1-CXCL9-CXCR3 axis PF-PH restoration this may unravel therapeutic strategy target disease.