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The combination of pharmacological modulators such as lumacaftor, tezacaftor, and elexacaftor restore CFTR activity at the plasma membrane and improve lung function in patients carrying CFTR mutations such as F508del, their effects on inflammation are less clear. This study aimed to investigate whether the inflammatory response in CF airway epithelial cells depends solely on Cl − transport or also on the structural integrity of the CFTR protein. We examined the effects of several CFTR modulators and wild-type CFTR overexpression on CFTR expression, trafficking, Cl − channel activity, and inflammation in human CF bronchial epithelial cells. Our results demonstrate that overexpression of wild-type CFTR fully restores Cl − secretion and normalizes the inflammatory response to levels observed in non-CF cells. In contrast, pharmacological correction of CFTR-F508del leads to partial recovery of Cl − transport and only limited reduction of inflammation. Structural analysis revealed that corrected CFTR-F508del fails to achieve the same conformational stability as wild-type CFTR. These findings suggest that beyond ion transport, the proper folding and structural integrity of CFTR are important for regulating inflammation, potentially through interactions with other cellular proteins involved in inflammatory pathways. This work highlights the need to develop therapeutic strategies that not only restore chloride channel function but also fully correct CFTR misfolding to better control inflammation in CF.

Standard Reference Material® (SRM®) 2585 can be considered as a model sample of settled indoor dust. At least 168 adsorbed chemicals were identified and quantified, generating a complex and potentially toxic mixture. Inhalable fractions PM10 and PM2.5 were isolated and compared to SRM® 2585 for their intrinsic properties and their respiratory toxicity using pertinent normal human bronchoepithelial (NHBE) cells. The intrinsic oxidative potential (OP) of SRM® 2585 and its subfractions was measured in acellular conditions, together with ROS generation and endotoxin content. For SRM® 2585 and PM10, cellular responses were evaluated on NHBE cells after 72 h exposure (1.1 to 110 µg/mL). The presence of endotoxins associated with an intrinsic prooxidant potential did not lead to the induction of an inflammatory response. Interestingly, cytokine production was decreased, strongly for IL-1β and to a lesser extent for IL-6. Only PM10 induced an acute toxicity. In parallel, mutagenicity was evaluated from organic extracts. Mutagenic profiles indicated the concomitant presence of nitro-PAHs in addition to the previously reported PAHs. This could be of concern for long-term health effects in a context of chronic exposure.

Standard Reference Material[sup.®] (SRM[sup.®] ) 2585 can be considered as a model sample of settled indoor dust. At least 168 adsorbed chemicals were identified and quantified, generating a complex and potentially toxic mixture. Inhalable fractions PM[sub.10] and PM[sub.2.5] were isolated and compared to SRM[sup.®] 2585 for their intrinsic properties and their respiratory toxicity using pertinent normal human bronchoepithelial (NHBE) cells. The intrinsic oxidative potential (OP) of SRM[sup.®] 2585 and its subfractions was measured in acellular conditions, together with ROS generation and endotoxin content. For SRM[sup.®] 2585 and PM[sub.10] , cellular responses were evaluated on NHBE cells after 72 h exposure (1.1 to 110 µg/mL). The presence of endotoxins associated with an intrinsic prooxidant potential did not lead to the induction of an inflammatory response. Interestingly, cytokine production was decreased, strongly for IL-1β and to a lesser extent for IL-6. Only PM[sub.10] induced an acute toxicity. In parallel, mutagenicity was evaluated from organic extracts. Mutagenic profiles indicated the concomitant presence of nitro-PAHs in addition to the previously reported PAHs. This could be of concern for long-term health effects in a context of chronic exposure.