Epidermal Growth Factor Receptor Blockade Mediates Smooth Muscle Cell Apoptosis and Improves Survival in Rats With Pulmonary Hypertension

Abstract

Background-We previously reported that administration of elastase inhibitors reverses fatal pulmonary arterial hypertension (PAH) in rats by inducing smooth muscle cell (SMC) apoptosis. We showed in pulmonary artery (PA) organ culture that the mechanism by which elastase inhibitors induce SMC apoptosis involves repression of matrix metalloproteinase (MMP) activity and subsequent signaling through ␣ v ␤ 3 -integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH. Methods and Results-In this study, we first showed in PA organ culture that MMP inhibition or ␣ v ␤ 3 -integrin blockade with agents in clinical and preclinical use (SC-080 and cilengitide, respectively) mediates SMC apoptosis and regression of medial hypertrophy. We also documented similar results with an EGFR tyrosine kinase inhibitor. We then induced PAH in rats by injection of monocrotaline and, at day 21, began a 2-week treatment with SC-080, cilengitide, or the EGFR inhibitor PKI166. No vehicle-or cilengitide-treated animal survived beyond 2 weeks. Administration of SC-080 resulted in 44% survival at 2 weeks, and PKI166 therapy resulted in 78% and 54% survival in daily or 3-times-weekly treated animals, respectively. Four weeks after cessation of PKI166, we documented survivals of 50% and 23% in the 2 treatment groups, associated with reductions in pulmonary pressure, right ventricular hypertrophy, and abnormally muscularized distal arteries. Conclusion-We

Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

“…MMP inhibition also did not improve epithelial repair and regeneration, suggesting that the epithelial lesion is likely primarily mediated by the alloimmune process. Interestingly, we found that administration of the MMP inhibitor during the developing phase of fibrosis (days [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], showed even better effects to reduce the airway obliteration. This result needs to be further confirmed and the underlying mechanism is unknown.…”

Molecular pathogenesis of pulmonary arterial hypertension

“…Normal BMPR2 signaling negatively regulates PDGF (52) and likely other growth-promoting factors implicated in the pathobiology of PAH, such as EGF (53). Since BMP4 induces differentiation of fetal lung fibroblasts into SMCs and inhibits their proliferation (54), lack of BMP4/BMPR2 interaction might expand the myofibroblast population of cells, accounting for the adventitial and intimal thickening of the PAs in PAH.…”

Role of Notch Signaling in Pulmonary Hypertension

“…Epidermal growth factor (EGF) was found to be co localized with Tenascin C, an ECM component, in the vascular lesions in PAH patients [50]. EGFR signaling was further demonstrated to be deregulated in MCT induced PAH rats and treatment with EGF receptor inhibitor, PKI166, induced PASMC apoptosis and increased survival of the rats [51]. Increased levels of basic fibroblast growth factor (bFGF/FGF--2) have been found in plasma and urine samples from PAH patients [52].…”

“…The current therapeutic approaches as well as above mentioned emerging strategies The muitikinase inhibitor, Sorafenib and the EGFR inhibitor, Iressa, have already shown to attenuate vascular remodeling in the animal models of PH [51,82] and appear promising for future therapy of PAH.…”