PT  - JOURNAL ARTICLE
AU  - Coste, Florence
AU  - Toussaint, Christian
AU  - Dubois, Mathilde
AU  - Courtois, Arnaud
AU  - Guibert, Christelle
AU  - Marthan, Roger
AU  - Savineau, Jean-Pierre
AU  - Muller, Bernard
AU  - Michel, Véronique
TI  - Role of the TrkA receptor in experimental severe pulmonary hypertension
AID  - 10.1183/13993003.congress-2015.PA4915
DP  - 2015 Sep 01
TA  - European Respiratory Journal
PG  - PA4915
VI  - 46
IP  - suppl 59
4099  - https://publications.ersnet.org//content/46/suppl_59/PA4915.short
4100  - https://publications.ersnet.org//content/46/suppl_59/PA4915.full
SO  - Eur Respir J2015 Sep 01; 46
AB  - Introduction. Pulmonary hypertension (PH) is a rare and severe disease, without any curative treatment, that ultimately leads to death. Our previous studies showed a role of the nerve growth factor NGF in severe pulmonary hypertension (SPH) by use of a rat model combining monocrotaline and chronic hypoxia. Using the same model, we have here studied whether the tropomyosin-related kinase A (TrkA) receptor, the NGF high-affinity receptor, is involved in SPH pathophysiology.Methods: SPH was induced in rats by a single injection of MCT (day (D) 1, 60 mg/kg, ip) followed by chronic hypoxia (CH, 0.5 atm, D3 to D28). The TrkA tyrosine-kinase inhibitor K252a was administrated curatively at D15-18-20-25-27 (80 µg/kg, ip). Mean pulmonary arterial pressure (mPAP) and Fulton index were assessed at D28. Pulmonary arterial reactivity, inflammation and remodelling were also evaluated.Results: In SPH rats, all the parameters studied were significantly increased compared to controls. The curative treatment with K252a totally reversed hyperreactivity to PHE, as well as pulmonary artery medial thickening and luminal occlusion. This treatment partially reversed the increase in mPAP (45% inhibition) and Fulton index (40% inhibition) and also partially inhibited increased secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) (27 and 33% inhibition respectively).Conclusions. We show that inhibition of the TrkA receptor in vivo displays curative effects in a rat model of SPH. These results confirm a role of NGF in SPH pathophysiology and demonstrate that targeting of the TrkA receptor may be of therapeutical interest in this disease.