The memory of airway epithelium damage in smokers and COPD patients

Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is a devastating lung disease, representing the third cause of mortality worldwide. In COPD, the bronchial epithelium displays several structural and functional abnormalities involving barrier integrity, polarity, cell differentiation and epithelial-to-mesenchymal transition, as well as inflammation. Although COPD is currently considered as an irreversible disease, the (ir)reversible nature of those changes ex vivo remains poorly known.MethodsThe persistence of COPD epithelial features was assessed in very long-term (10 weeks) primary cultures of air/liquid interface (ALI)-reconstituted airway epithelium from non-smoker controls, smoker controls, and COPD patients. The role of inflammation in promoting this phenotype was also explored by stimulating ALI cultures with a cytokine mix of TNF-α, IL-6 and IL-1β.ResultsAlmost all epithelial defects (barrier dysfunction, impaired polarity, lineage abnormalities) observed in smokers and COPD persisted in vitro up to week 10, except IL-8 release and epithelial-to-mesenchymal transition which declined over time. Cytokine treatment induced COPD-like changes and was able to reactivate epithelial-to-mesenchymal transition in COPD cells.ConclusionsThe airway epithelium from smokers and COPD patients displays a memory of its native state and previous injuries by cigarette smoking, which is multidimensional and sustained for years, therefore probably residing in basal stem cells.

Secretory Immunoglobulin A Immunity in Chronic Obstructive Respiratory Diseases

“…Apart from pIgR downregulation in situ, in COPD airway tissues, we also showed that the airway epithelium redifferentiated in vitro in air/liquid-interface displays decreased pIgR expression and SC apical release, as well as impaired IgA transepithelial routing of d-IgA [68]. More recently, we demonstrated that the dysregulation of the pIgR/SC system in COPD is durably imprinted in the COPD airway epithelium, as long-term cultures (up to 10 weeks) of ALI-redifferentiated COPD airway epithelial cells exhibit persistent decreases in pIgR expression and SC release, along with impaired pIgR mRNA levels [74], corroborating previous findings obtained at 4 weeks of ALI culture [83]. Interestingly, increased IL-6 and BAFF/APRIL-TACI signalling have been observed in COPD at the epithelium level, driving class switch recombination towards IgA [88]; a feature that was also observed in smokers without COPD [92].…”

“…For instance, pIgR mRNA levels are increased in ex-smokers' lungs. This increase is however not observed at the protein level, or in situ nor in air/liquid interface cultures of primary human bronchial epithelial cells exposed to cigarette smoke (CS) or derived from smokers [68,74]. These data suggest that the CS exposure acts as a player in the regulation of pIgR gene expression in vivo, which is further submitted to post-transcriptional modifications that have not been much explored so far.…”

Role of Respiratory Epithelial Cells in Allergic Diseases

“…Interestingly, when basal epithelial cells were cultured from these patients, the type 2 signatures persisted ex vivo through serial passage, suggesting an allergic inflammatory memory composed of several IL-4-induced cytokines, even in the absence of cytokine stimulation [143]. A recently published preprint using air liquid interphase cultures from controls and COPD patients identified long-term epithelial defects as measured by barrier dysfunction, impaired polarity, and lineage abnormalities that persisted in vitro beyond ten weeks [144]. In conclusion, there are lessons to be learned from these types of study designs in order to distinguish the most persistent signatures from those that fade, representing an exciting opportunity to link human scRNA-seq studies with functional experiments using stem-cell derived models.…”

Airway Basal Cells, Protectors of Epithelial Walls in Health and Respiratory Diseases

“…These observations are in line with previous studies in skin and intestine, where post-inflamed mice showed faster healing after wounding compared to naïve mice and organoids from intestinal epithelial stem cells of mice on a high-fat diet grew abnormally, respectively ( 39 , 135 ). Further indications for inflammatory memory in airway epithelial cells include the observation that barrier and junctional defects as well as ciliated cell hypoplasia persist in air-liquid interface (ALI) airway epithelial cell cultures from smoker and COPD patients ( 136 ). In addition, Martin et al demonstrated in vitro that human bronchial epithelial cells (i.e., BEAS-2B cell line) remember infection as they can induce either a trained or tolerant response, dependent on the combination of primary and secondary trigger, meaning that their secondary response was modulated after the initial trigger ( 137 ).…”