Reversal of experimental severe pulmonary hypertension by NGF inhibition - 04/04/15

NGF expression is significantly increased in a new rat model of severe pulmonary hypertension (SPH) combining injection of monocrotaline (MCT) and chronic hypoxia (CH). Administration of anti-NGF blocking antibodies in vivo in this SPH model prevented, at least partially, increase in pulmonary arterial pressure (PAP), pulmonary arterial inflammation, remodelling, and hyperreactivity. In the present work, we studied whether anti-NGF blocking antibodies also displayed curative effects in this SPH model.

SPH was induced in rats by a single injection of MCT [day (D)1, 60mg/kg] followed by chronic hypoxia (CH, 0.5 atm, D3 to D28). Anti-NGF blocking antibodies (10μg/kg IP) were administered curatively at D15-19-22-26. Mean pulmonary arterial pressure (mPAP) and Fulton index (index of cardiac remodelling) were assessed at D28. Secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) from rat pulmonary arteries were evaluated by Elisa. Pulmonary arterial reactivity to phenylephrine (PHE) or prostaglandin F2α (PGF2α) was evaluated ex vivo. Pulmonary arterial remodelling was assessed by measuring medial thickness and luminal occlusion (eosin-hematoxylin or van Gieson stainings).

In the SPH model, mPAP and Fulton index were significantly increased compared to controls. Increased secretions of IL-1β and TNF-α were observed, as well as pulmonary arterial remodelling and hyperreactivity to both PHE and PGF2α. The curative treatment with anti-NGF blocking antibodies totally reversed TNF-α increased secretion, pulmonary arterial medial thickness, luminal occlusion and hyperreactivity to PHE. This curative protocol also partially reduced increased mPAP, IL-1β increased secretion, hyperreactivity to PGF2α and cardiac remodelling.

We show that inhibition of NGF in vivo in a new rat model of severe PH partially reversed increased mPAP and cardiac remodelling. Moreover, our results show that NGF plays a role in various pathophysiological aspects of severe PH, and may therefore be of therapeutical interest in this disease.