Impacts of Particulate Air Pollution on Repair and Abnormal Inflammation in Copd: the Role of Itih4 and the Regeneration Pathways

Chronic obstructive pulmonary disease (COPD) is an abnormal inflammatory airway disease with systemic inflammation and manifestations, currently lacking effective treatment to modify its progression and to decrease mortality. Pathogenesis of COPD also includes premsture aging and epitheial cell apoptosis, as well as excessive matrix degradation and impairement in repair. The latter also deteriorates the abnormal inflammation. Particulate Matter (PM) has long been implicted in COPD with poor understood mechanisms. We have previously found that PM is able to induce oxidative protein, inhibit the Wnt pathway and induce apoptosis of lung epithelium in mice. Analysis of serum from human revealed that inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) protein is reduced in COPD patients, which was strongly correlated to PM. In this project, we will further investigate the functional role of ITIH4 in COPD in the context of PM and its regulatory mechanisms. This is a 3-year project with 3 specific aims: (1), to confirm the protective roles of ITIH4 in inflammation, apoptosis, pulmonary epithelial repair, and regeneration in COPD and normal subjects; (2), to explore the mechanisms whereby ITIH4 is down regulated in COPD and responses to inflammation and to environmental stress, e.g. PM in inflammatory and lung/airway epithelial cells; (3), to investigate the action of ITIH4 in COPD animal models and human COPD specimens. We will enroll 180 subjects, including 30 each of normal non-smokers, healthy smokers and stage I-IV COPD patients. ITIH4 and the related molecules will be correlated to the clinical data. PBMC, MDM, monocyte cell lines and respiratory epithelial cell lines will be used to explore the mechanism. BALB/c mice exposed to PM2.5 or PM10 using a cigarette smoke chamber will be used as animal models. This study will not only extend our knowledge into the mechanism whereby PM is implicated in abnormal inflammation, pulmonary injury and repair but also will possibly provide a novel target or therapeutic direction for developing effective therapy for pulmonary diseases including COPD.