Inflammation and Oxidative Stress Induce NGF Secretion by Pulmonary Arterial Cells through a TGF-beta 1-Dependent Mechanism

Expression of the nerve growth factor NGF is increased in pulmonary hypertension (PH). We have here studied whether oxidative stress and inflammation, two pathological conditions associated with transforming growth factor-beta 1 (TGF-beta 1) in PH, may trigger NGF secretion by pulmonary arterial (PA) cells. Effects of hydrogen peroxide (H2O2) and interleukin-1 beta (IL-1 beta) were investigated ex vivo on rat pulmonary arteries, as well as in vitro on human PA smooth muscle (hPASMC) or endothelial cells (hPAEC). T beta RI expression was assessed by Western blotting. NGF PA secretion was assessed by ELISA after TGF-beta 1 blockade (anti-TGF-beta 1 siRNA, TGF-beta 1 blocking antibodies, T beta RI kinase, p38 or Smad3 inhibitors). T beta RI PA expression was evidenced by Western blotting both ex vivo and in vitro. H2O2 or IL-1 beta significantly increased NGF secretion by hPASMC and hPAEC, and this effect was significantly reduced when blocking TGF-beta 1 expression, binding to T beta RI, T beta RI activity, or signaling pathways. In conclusion, oxidative stress and inflammation may trigger TGF-beta 1 secretion by hPASMC and hPAEC. TGF-beta 1 may then act as an autocrine factor on these cells, increasing NGF secretion via T beta RI activation. Since NGF and TGF-beta 1 are relevant growth factors involved in PA remodeling, such mechanisms may therefore be relevant to PH pathophysiology.