PT  - JOURNAL ARTICLE
AU  - Fadila Telarevic Cero
AU  - Karl Otto Larsen
AU  - Vigdis Hillestad
AU  - Ivar Sjaastad
AU  - Arne Yndestad
AU  - Pål Aukrust
AU  - Egil Lien
AU  - Else Marit Løberg
AU  - Geir Christensen
AU  - Ole Henning Skjønsberg
TI  - Inflammasome ASC-knock out attenuates the development of pulmonary hypertension caused by chronic alveolar hypoxia
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - P307
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/P307.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/P307.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - Background: Inflammasomes are molecular platforms which are part of the innate immunity and the best characterized is the NLRP3 inflammasome consisting of the receptor (NLRP3), the adaptor protein (ASC) and caspase-1, the effector cysteine protease which activate IL-18 and IL-1β. Increased levels of interleukin (IL)-18 have been found during experimental alveolar hypoxia (K.O. Larsen et al. Cardiovasc Res, 2008), which leads to pulmonary hypertension.Objective: To study role of NLRP3 inflammasome in chronic hypoxia induced pulmonary hypertension.Methods: Active caspase-1, IL-18 and IL-1β were measured by Western blot analysis of lung homogenates in WT, NLRP3-/- and ASC-/- mice exposed to 1 months of hypoxia in a tightly sealed chamber containing 10% oxygen. Right ventricular systolic pressure (RVSP) was measured with a microtipped transducer catheter after 3 months of hypoxia exposure.Results: Chronic hypoxia induced increased protein levels of caspase-1, IL-18 and IL-1β in WT and NLRP3-/- mice. However, hypoxia-induced activation of the inflammasome was absent in ASC-/- mice shown by no increase of active caspase-1, IL-18 or IL-1β. RVSP of ASC-/- exposed to hypoxia was significantly lower than WT hypoxia (40.8±1.5 mmHg versus 55.8±2.4 mmHg, p‹0.001), demonstrating a lesser degree of pulmonary hypertension. RVSP of NLRP3-/- exposed to hypoxia was not significantly altered compared to WT hypoxia (52.4±2.3 mmHg versus 55.8±2.4 mmHg).Conclusions: Altogether, our results show that ASC-/- mice are protected against hypoxia-induced pulmonary hypertension, suggesting inflammasome activation to be involved in the pathogenesis of the disease.