Bone Morphogenic Proteins and Their Antagonists in the Lower Airways of Stable COPD Patients

SIMPLE SUMMARY: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, usually progressive, that is associated with the development of an increased inflammatory response in the airways and lung parenchyma. Reduction in the small airways and destruction of the lung parenchyma, due to emphysema, are frequently associated with the increasing severity of the disease. Cigarette smoke is considered the major cause of COPD in Westernized countries. Strategies to identify and combat the main alterations characterizing this disease are under constant investigation. Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs, including the lungs. For this reason, we studied the expression and localization of BMPs and their antagonists in the large and small airways and lung parenchyma of COPD patients, control smokers (CS), and control non-smokers (CNS). In COPD, compared to CNS, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium of large airways, while BMP4 was decreased. In some compartments of the peripheral lung, CRIM1 and chordin were significantly decreased compared to CNS. As testified by our in vitro experiments, the typical inflammation occurring in COPD may decrease BMP4 expression in bronchial epithelial cells; hence, treatment of these cells with BMP4 protein could reduce its proliferative capability. We also showed an imbalance between BMPs and their antagonists in the lungs of stable COPD patients. These alterations may influence the remodeling process of the diseased lung as the disease progresses. ABSTRACT: Background: Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs. Objective: To determine transcriptomic and protein expression of BMPs and their antagonists in stable COPD. Methods: We measured the expression and localization of BMPs and some relevant antagonists in bronchial biopsies of stable mild/moderate COPD (MCOPD) (n = 18), severe/very severe COPD (SCOPD) (n = 16), control smokers (CS) (n = 13), and control non-smokers (CNS) (n = 11), and in lung parenchyma of MCOPD (n = 9), CS (n = 11), and CNS (n = 9) using immunohistochemistry and transcriptome analysis, in vitro after the stimulation of the 16HBE cells. Results: In bronchial biopsies, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium and lamina propria of COPD patients. BMP4 expression was decreased in the bronchial epithelium of SCOPD and MCOPD compared to CNS. Lung transcriptomic data showed non-significant changes between groups. CRIM1 and chordin were significantly decreased in the alveolar macrophages and alveolar septa in COPD patients. External 16HBE treatment with BMP4 protein reduced the bronchial epithelial cell proliferation. Conclusions: These data show an imbalance between BMP proteins and their antagonists in the lungs of stable COPD. This imbalance may play a role in the remodeling of the airways, altering the regenerative–reparative responses of the diseased bronchioles and lung parenchyma.