Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Jandl, K; Marsh, LM; Mutgan, AC; Crnkovic, S; Valzano, F; Zabini, D; Hoffmann, J; Foris, V; Gschwandtner, E; Klepetko, W; Prosch, H; Flick, H; Brcic, L; Kern, I; Heinemann, A; Olschewski, H; Kovacs, G; Kwapiszewska, G.
Impairment of the NKT-STAT1-CXCL9 Axis Contributes to Vessel Fibrosis in Pulmonary Hypertension Caused by Lung Fibrosis.
Am J Respir Crit Care Med. 2022; 206(8):981-998
Doi: 10.1164/rccm.202201-0142OC
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PubMed
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- Leading authors Med Uni Graz
- Jandl Katharina
- Kwapiszewska-Marsh Grazyna
- Co-authors Med Uni Graz
- Brcic Luka
- Crnkovic Slaven
- Flick Holger
- Foris Vasile
- Gschwandtner Elisabeth
- Heinemann Akos
- Hoffmann Julia
- Kovacs Gabor
- Marsh Leigh
- Mutgan Redolfi Ayse Ceren
- Olschewski Horst
- Valzano Francesco
- Zabini Diana
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- Abstract:
- 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 fibrosis and inflammation are often present in PH, but the underlying mechanisms are still not well understood. Objectives: To identify a novel functional link between natural killer T (NKT) cell activation and vascular fibrosis in PF-PH. Methods: Multicolor flow cytometry, secretome, and immunohistological analyses were complemented by pharmacological NKT cell activation in vivo, in vitro, and ex vivo. Measurements and Main Results: In pulmonary vessels of patients with PF-PH, increased collagen deposition was linked to a local NKT cell deficiency and decreased IL-15 concentrations. In a mouse model of PH caused by lung fibrosis, pharmacological NKT cell activation using a synthetic α-galactosylceramide analog (KRN7000) restored local NKT cell numbers and ameliorated vascular remodeling and right ventricular systolic pressure. Supplementation with activated NKT cells reduced collagen deposition in isolated human pulmonary arterial smooth muscle cells (hPASMCs) and in ex vivo precision-cut lung slices of patients with end-stage PF-PH. Coculture with activated NKT cells induced STAT1 signaling in hPASMCs. Secretome analysis of peripheral blood mononuclear cells identified CXCL9 and CXCL10 as indicators of NKT cell activation. Pharmacologically, CXCL9, but not CXCL10, potently inhibited collagen deposition in hPASMCs via the chemokine receptor CXCR3. Conclusions: Our results indicate that the absence of NKT cells impairs the STAT1-CXCL9-CXCR3 axis in PF-PH and that restoration of this axis by NKT cell activation may unravel a novel therapeutic strategy to target vascular fibrosis in interstitial lung disease.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Humans - administration & dosage
- Mice - administration & dosage
- Chemokine CXCL9 - therapeutic use
- Collagen - metabolism
- Hypertension, Pulmonary - drug therapy
- Interleukin-15 - therapeutic use
- Leukocytes, Mononuclear - metabolism
- Lung Diseases, Interstitial - pathology
- Pulmonary Fibrosis - administration & dosage
- STAT1 Transcription Factor - administration & dosage
- Natural Killer T-Cells - administration & dosage
- Find related publications in this database (Keywords)
- interstitial lung disease
- immunotherapy
- vascular remodeling
- vascular fibrosis