Rationale: Cigarette smoke (CS) is a risk factor for chronic lung disease (CLD). The first barrier against CS is the airway epithelium. While transcriptome changes in the bronchial epithelium following CS exposure have been reported, proteomic data is lacking.

Objective: To explore CS-induced protein changes in (1) bronchoalveolar lavage fluid (BALF) of current-, ex-, and never-smokers of CLD patients, and (2) following CS exposure of primary human bronchial epithelial cells (phBECs)1 for the discovery of mechanisms in CS-induced lung disease.

Methods: PhBECs chronically exposed to CS extract (CSE) and BALF2 from the three patient groups were subjected to MS/MS-based proteomics, to pathway enrichment analysis (PEA), and selected findings were validated.

Results: CS induced transient and persistent changes in BALF with a considerable overlap between transient changes in phBECs and BALF. Numerous xenobiotic-metabolising enzymes were among the transient changes in vitro. PEA of the phBECs suggested NUPR1 as a central regulator of CS-induced transient changes and its inhibition increased cytotoxicity in phBECs.

Conclusions: CS exposure results in transient and persistent protein changes in BALF. While bronchial epithelial cells are likely the main origin of transient changes, the source of the persistent changes is unknown. Future research will determine the cellular sources of persistent changes and examine alterations by CS in the pathophysiology of various CLD. Discovering disease- and cell type-specific mechanisms underlying the persistent response to CS may lead to the development of new CLD treatment approaches.

1Mastalerz, M et al. Am J Phys Lung Cell Mol Phys 2022, L129-48

2Mayr, C et al. EMBO Mol Med 2021, 13:e12871