RT Journal Article
SR Electronic
T1 Role of the TrkA receptor in experimental severe pulmonary hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA4915
DO 10.1183/13993003.congress-2015.PA4915
VO 46
IS suppl 59
A1 Florence Coste
A1 Christian Toussaint
A1 Mathilde Dubois
A1 Arnaud Courtois
A1 Christelle Guibert
A1 Roger Marthan
A1 Jean-Pierre Savineau
A1 Bernard Muller
A1 Véronique Michel
YR 2015
UL http://erj.ersjournals.com/content/46/suppl_59/PA4915.abstract
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.