Role of lysyl oxidases in pathogenesis of pulmonary emphysema

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) includes pulmonary emphysema (PE), chronic bronchitis, certain types of bronchiectasis, and sometimes asthma. Abnormal elastic fiber polymerization and degradation are from characteristic properties of PE. The copper-dependent lysyl oxidases play a role in the formation and accumulation of elastic fibers in the extracellular matrix. Aims and objectives: There are no data about the efficacy of lysyl oxidases in the development of PE in humans. We focused on the relationship between LOX, LOXL1, LOXL2 and PE pathogenesis in COPD patients. Methods: Alterations at the protein levels of LOX, LOXL1, LOXL2, COMMD1 (regulator protein of copper homeostasis) and hypoxia-inducible factor 1-alpha (HIF-1α, a transcription factor of LOX genes) were for the first time investigated to determine their effects on emphysema pathogenesis by Western blotting and immunohistochemical methods in lung of COPD patients (n=19) with lung cancer. Results: Enlargement alveoli, thinning and disruptions in alveolar wall, a lot of accumulated macrophages in alveolar lumen and increased HIF-1α immunoreactivity were observed in emphysematous areas. Furthermore, in these tissues, levels of elastin, LOX, LOXL1, LOXL2, HIF-1α and COMMD1 decreased when compared to non-emphysematous areas. Conclusions: We think that reductions of HIF-1α levels in PE led to decreases in protein levels of activated LOX, LOXL1 and LOXL2, and abnormalities in elastic fiber biology. In emphysematous areas, HIF-1α activation induced by decreased COMMD1 protein can contribute to the generation of disease pathogenesis. Approaches made to increase activated LOXs and COMMD1 can be effective for the regression of PE.