Study on serum marker for pulmonary arterial hypertension associated with connective tissue disease

BackgroundPulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases (CTDs). In spite of the similiarity to idiopathic PAH (IPAH) in pathology, drug response and prognosis of CTD-PAH is much poorer. Some patients got relief after steroid/immuno-suppressive therapy, indicating a more pronounced immunity and inflammation pathway in CTD-PAH. As PAH becoming one of the main causes of morbid-mortality in CTD, it is important to find serum markers for this vascular problem.Objective and methods1. To verify the pathogenic role of anti-moesin antibody in PAH by immunizing SD rats with human moesin antigen.2. To define the potential role of macrophage migration inhibitory facor (MIF) as a serum biomarker for CTD-PAH by detecting its serum level through ELISA and comparing it between CTD-PAH and CTD-non PAH patients.3. To explore the role of MIF in the pathogenesis of PAH preliminarily by dedecting its level in lung tissues through western blot and comparing it between monocrotaline induced PAH rats and normal rats.4. To define the potential role of soluble endoglin (sENG) as a serum biomarker for CTD-PAH by detecting its serum level through ELISA and comparing it between CTD-PAH and CTD-non PAH patients.Results1. Rats immunized by human moesin antigen had a significantly higher level of mean pulmonary arterial pressure than normal (p<0.01). Pathologic study showed there was thickening of the walls of medium sized arterioles (about100um in diameter) and inflammation in the lung. Rat immunized purely by complete/incomplete Freund’s adjuvant have slightly elevated mPAP, and there were also some inflammation cells scattered in the lung.2. Serum level of MIF was significantly increased in SLE and SSc patents (P=0.012,0.022respectively), but there were no differences between SLE/SSc-PAH and SLE/SSc-non PAH patients. Patients in an active state of SLE had a significantly higher level of MIF than those in quienscent state (P=0.001). SSc patients who had digital ulcers had an elevated level of MIF than those who had not (P=0.033).3. There was no difference of MIF level in the lung tissues between MCT-PAH rats and normal rats.4. Serum level of sENG was significantly increased in SLE and SSc patents (P=0.001,0.046respectively), but there were no differences between SLE/SSc-PAH and SLE/SSc-non PAH patients. We haven’t find any clinical relevance of the elevated serum level of sENG in SLE yet. SSc patients who had telangiectasis had an elevated level of MIF than those who had not (P=0.026).Conclusions1. Anti-moesin antibody might play a pathogenic role in PAH, but still need to be verified by further study.2. Higher level of serum MIF might indicate an active state of SLE while it may be related to digital ulcers in SSc. We failed to prove MIF have a predictive potiential for PAH in CTD.3. It seems like MIF didn’t participate in the pathogenesis of PAH as there was no difference of MIF level in lung tissues between MCT-PAH and normal rats. But further investigation is needed.4. Higer level of sENG in SLE might be related to endothelial cell dysfunction. In SSc however, elevated sENG indicate telangiectasis. We failed to improve sENG have a predictive potiential for PAH in CTD.