The copper dependent-lysyl oxidases contribute to the pathogenesis of pulmonary emphysema in chronic obstructive pulmonary disease patients

Abstract

Abnormalities in the elastic fiber biology are seen in pulmonary emphysema (PE). The copper-dependent lysyl oxidases regulate the production and accumulation of elastic fibers in the connective tissue. This study focused on the relationship between lysyl oxidase (LOX), LOX-like protein 1 (LOXL1), and LOXL2 and PE pathogenesis. Lung samples with or without PE from patients with chronic obstructive lung disease (n=35) were used. Protein levels of elastin, LOX, LOXL1, LOXL2, hypoxia inducible factor 1-alpha (HIF-1α), copper metabolism domain containing-1 (COMMD1), and phosphatase and tensin homolog (PTEN) were assayed using microscopic and biochemical methods The emphysematous areas were characterized by enlargement of the alveoli, destruction of the alveolar structure, accumulation of macrophages in the alveolar lumens, and showed increased HIF-1α immunoreactivity. Additionally, the emphysematous areas had significantly lower elastin, LOX, LOXL1, LOXL2, HIF-1α, COMMD1, and PTEN protein levels than the non-emphysematous areas. We suppose that the reductions in the HIF-1α levels led to decreases in the protein levels of active LOX, LOXL1, and LOXL2. These decreases might cause abnormalities in the elastic fiber biology. HIF-1α activation induced by decreased COMMD1 and protease activation induced by decreased PTEN might contribute to the development of PE. Finally, methods aimed at increasing the protein levels of LOXs, COMMD1 and PTEN might be effective for treating PE.