Alveolar type II (ATII) cells produce and secrete the pulmonary surfactant. They have stem cell potential, proliferate and restore the epithelium after damage. Emphysema is characterized by alveolar wall destruction. It is caused by cigarette smoking and second hand smoke. High oxidative stress induced by this exposure leads to ATII cell injury, mitochondrial and nuclear DNA damage. DNA double-strand breaks (DSBs) pose the most serious threat to the genomic and mitochondrial DNA. Mitochondrial DNA (mtDNA) is more susceptible to oxidative damage than nuclear DNA due to the lack of histones that serve as a barrier against damaging factors as well as limited DNA repair capacity. Failure to repair mtDNA DSBs can trigger a formation of mutations, deletions and mitophagy. Moreover, damaged mtDNA can be secreted from mitochondria to the cytoplasm and extracellular space via exosomes. Exosomes are small membrane vesicles that are released from the cell under normal or pathological conditions. They also serve as signaling vehicles by delivering proteins, DNA and RNA, to the recipient cells leading to alteration of their gene expression, proliferation, and differentiation. Furthermore, it has been reported that CD147 regulates complex I activity in mitochondria and cell apoptosis by interacting with mitochondrial proteins. CD147 is an extracellular matrix metalloproteinase (MMP) inducer and is known to stimulate MMPs expression. We detected high mtDNA and CD147 levels in ATII cell-derived exosomes obtained from patients with emphysema. We will use monoclonal antibody against CD147 to block its harmful function. Our hypothesis is tinhaetxmotsDoNmAesansdecCrDet1e4d7by ATII cells in emphysema induce injury in the recipient cells. Monoclonal antibody against CD147 will block circulation of exosomes with harmful content.
In Specific Aim #1 we will determine the function of ATII cell-derived exosomes obtained from emphysema patients. We will study the role of exosomal mtDNA and CD147 on the recipient ATII cells.
In Specific Aim #2, we will determine whether monoclonal antibody blocking CD147 will decrease the harmful function of exosomes on the recipient cultured ATII cells. Upon completion of the proposed study, we will have characterized the function of exosomes secreted by ATII cells in emphysema and their effect on the recipient cells. Monoclonal antibody against exosomal CD147 can provide a new therapeutic strategy against this disease progression.
Second hand smoke and cigarette smoking are the most common cause of pulmonary emphysema. This project addresses the role of exosomes in this disease progression. The pathogenic mechanisms of this disease are still not fully understood and there is limited effective therapy. We propose to determine the inflammatory role of exosomes in emphysema. This study has a clinical importance and can lead to novel therapeutic strategies to target exosomes to slow this disease development.
