Format

Send to

Choose Destination
Am J Physiol Lung Cell Mol Physiol. 2019 Jun 1;316(6):L999-L1012. doi: 10.1152/ajplung.00322.2018. Epub 2019 Mar 25.

Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension.

Author information

1
Department of Pulmonary Medicine, Oslo University Hospital Ullevål and University of Oslo , Oslo , Norway.
2
Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo , Oslo , Norway.
3
K. G. Jebsen Center for Cardiac Research and Center for Heart Failure Research, University of Oslo , Oslo , Norway.
4
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo , Oslo , Norway.
5
Department of Pathology, Oslo University Hospital Ullevål and University of Oslo , Oslo , Norway.
6
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet and University of Oslo , Oslo , Norway.

Abstract

Lung diseases with hypoxia are complicated by pulmonary hypertension, leading to heart failure and death. No pharmacological treatment exists. Increased proinflammatory cytokines are found in hypoxic patients, suggesting an inflammatory pathogenesis. Caspase-1, the effector of the inflammasome, mediates inflammation through activation of the proinflammatory cytokines interleukin (IL)-18 and IL-1β. Here, we investigate inflammasome-related mechanisms that can trigger hypoxia-induced pulmonary hypertension. Our aim was to examine whether caspase-1 induces development of hypoxia-related pulmonary hypertension and is a suitable target for therapy. Wild-type (WT) and caspase-1-/- mice were exposed to 10% oxygen for 14 days. Hypoxic caspase-1-/- mice showed lower pressure and reduced muscularization in pulmonary arteries, as well as reduced right ventricular remodeling compared with WT. Smooth muscle cell (SMC) proliferation was reduced in caspase-1-deficient pulmonary arteries and in WT arteries treated with a caspase-1 inhibitor. Impaired inflammation was shown in hypoxic caspase-1-/- mice by abolished pulmonary influx of immune cells and lower levels of IL-18, IL-1β, and IL-6, which were also reduced in the medium surrounding caspase-1 abrogated pulmonary arteries. By adding IL-18 or IL-1β to caspase-1-deficient pulmonary arteries, SMC proliferation was retained. Furthermore, inhibition of both IL-6 and phosphorylated STAT3 reduced proliferation of SMC in vitro, indicating IL-18, IL-6, and STAT3 as downstream mediators of caspase-1-induced SMC proliferation in pulmonary arteries. Caspase-1 induces SMC proliferation in pulmonary arteries through the caspase-1/IL-18/IL-6/STAT3 pathway, leading to pulmonary hypertension in mice exposed to hypoxia. We propose that caspase-1 inhibition is a potential target for treatment of pulmonary hypertension.

KEYWORDS:

caspase-1; hypoxia; pulmonary hypertension; smooth muscle cell

PMID:
30908936
DOI:
10.1152/ajplung.00322.2018

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center