Rcn3 Suppression Was Responsible for Partial Relief of Emphysema as Shown by Specific Type II Alveolar Epithelial Cell Rcn3 CKO Mouse Model

Int J Chron Obstruct Pulmon Dis. 2021 Jan 26:16:147-158. doi: 10.2147/COPD.S272711. eCollection 2021.

Abstract

Background: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow limitation, is a highly prevalent lung disease worldwide and imposes increasing disease burdens globally. Emphysema is one of the primary pathological features contributing to the irreversible decline of pulmonary function in COPD patients, but the pathogenetic mechanisms remain unclear. Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum (ER) lumen protein localized in the secretory pathway of living cells. Rcn3 in type II alveolar epithelial cell (AECIIs) has been reported to play a critical role in regulating perinatal lung development and bleomycin-induced lung injury-repair processes. We hypothesized that Rcn3 deficiency is associated with the development of emphysema during COPD, which is associated with the dysfunction of injury-repair modulated by alveolar epithelial cells.

Materials and methods: We examined Rcn3 expression in lung specimens from COPD patients and non-COPD control patients undergoing lung lobectomy or pneumonectomy. Two mouse models of emphysema were established by cigarette smoke (CS) exposure and intratracheal instillation of porcine pancreatic elastase (PPE). Rcn3 expression was detected in the lung tissues from these mice. Furthermore, conditional knockout (CKO) mice with Rcn3 deletion specific to AECIIs were used to explore the role of Rcn3 in PPE-induced emphysema progression. Rcn3 protein expression in lung tissues was evaluated by Western blot and immunohistochemistry. Rcn3 mRNA expression in lung tissues was detected by qPCR.

Results: Rcn3 expression was significantly increased in the lung specimens from COPD patients versus non-COPD patients and the level of Rcn3 increase was associated with the degree of emphysema. Rcn3 expression were also significantly up-regulated in both CS-induced and PPE-induced emphysematous mouse lungs. Moreover, the selective ablation of Rcn3 in AECIIs significantly alleviated severity of the mouse emphysema in response to intratracheal installation of PPE.

Conclusion: Our data, for the first time, indicated that suppression of Rcn3 expression in AECIIs has a beneficial effect on PPE-induced emphysema.

Keywords: COPD; Rcn3; emphysema; type II alveolar epithelial cell.

MeSH terms

  • Alveolar Epithelial Cells
  • Animals
  • Calcium-Binding Proteins
  • Emphysema*
  • Humans
  • Lung
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Disease, Chronic Obstructive* / genetics
  • Pulmonary Emphysema* / chemically induced
  • Pulmonary Emphysema* / genetics
  • Swine

Substances

  • Calcium-Binding Proteins
  • RCN3 protein, mouse

Grants and funding

This work was supported by National Natural Science Foundation of China (No. 81641004 to Qiuhong Fang), and was supported in part by National Natural Science Foundation of China (No. 81770062 to Jiawei Jin).