Inhibition Of PPAR γ Activators Rosiglitazone And ATRA On Matrix Metalloproteinase-9 In The Lungs Of COPD Rats

Matrix metalloproteinases ( MMPs ) are a family of neutralproteinases that are minimally composed of a prodomain that requirescleavage for activation of a zinc-binding catalytic domain. MMPs havebeen proposed to be a key in causing the degradation of lung extracellularmatrix (ECM) in chronic obstructive pulmonary disease (COPD) becauseof their capacity to cleave structural proteins such as collagens and elastin.MMP-9 (gelatinase B, 92-kD type IV collagenase) is present in lowquantity in the healthy adult lungs, but much more abundant in COPDlungs. Inhibiting the expression and activity of MMP-9 is possiblybeneficial to prevent and treat COPD. Peroxisome proliferator-activatedreceptors (PPARs) are members of a nuclear hormonereceptor/transcription factor superfamily. Rosiglitazone is a potent ligandfor PPARγ, Our previous experiments showed that it prevent frompathogenesis of COPD in rats administered with lipopolysaccharide (LPS)and smoked. All-trans retinoic acid (ATRA) may interfere with thepathogensis of COPD by regulating proteases/antiproteases balance andpromoting matrix regeneration. This study was designed to evaluate theimpact of RGZ and ATRA on MMP-9 of lung tissue in rats with COPD.Major results are followed: The COPD rat models (COPD rats) were established by intratrachealinstillation of LPS twice and smoked everyday for 1 hour for 4 weeks.Some of COPD rats were administered with RGZ (20μg/ml, 1ml for onceevery rat) or ATRA before they were smoked. The lungs of all COPD ratsand control healthy rats were sampled on day 29th to analyze activity,quantity and mRNA expression. Gelatin zymography showed that MMP-9activity of the lung homogenate of COPD rats is more potent than that ofcontrol rats' homogenate . ELISA showed that the MMP-9 concentration ofthe lung homogenate of COPD rats is higher than that of control rats'homogenate. RT-PCR showed that MMP-9mRNA expression of COPDrats' lungs was more abundant than that of control rats' lungs. Both RGZand ATRA inhibited the expression and activity of MMP-9 in COPD rats.The inhibition of MMP-9 activity is coherent with the inhibition of MMP-9secretion and mRNA expression. To further investigate the effects of RGZ and ATRA on MMP-9 withinthe lung microenvironment, alveolar macrophages (AM) recovered fromthe Bronchoalveolar lavage (BAL) of COPD or control rats were culturedwith RGZ and ATRA in vitro. RGZ and ATRA significantly reduced boththe production and enzyme activity of MMP-9 secreted by AM. Conclusion MMP-9 was induced to express and mediate degradationof gelatin in lungs by intratracheal instillation of LPS twice and smokingwith cigarettes in rats. The treatment with RGZ and ATRA reducedtranscription of MMP-9, leading to decrease in its quantity and activity. It istrue for LPS-stimulated macrophages derived from BALF of COPD rats.The results showed that Inhibition of MMP-9 may be one of themechanisms for prevention and treatment of COPD of RGZ and ATRA.