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CC16 augmentation reduces exaggerated COPD-like disease in Cc16-deficient mice

Low Club Cell 16 kDa protein (CC16) plasma levels are linked to accelerated lung function decline in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke–exposed (CS-exposed) Cc16(–/–) mice have exaggerated COPD-like disease associated with increased NF-κB activation in their...

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Detalles Bibliográficos
Autores principales: Rojas-Quintero, Joselyn, Laucho-Contreras, Maria Eugenia, Wang, Xiaoyun, Fucci, Quynh-Anh, Burkett, Patrick R., Kim, Se-Jin, Zhang, Duo, Tesfaigzi, Yohannes, Li, Yuhong, Bhashyam, Abhiram R., Li, Zhang, Khamas, Haider, Celli, Bartolome, Pilon, Aprile L., Polverino, Francesca, Owen, Caroline A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070105/
https://www.ncbi.nlm.nih.gov/pubmed/36787195
http://dx.doi.org/10.1172/jci.insight.130771
Descripción
Sumario:Low Club Cell 16 kDa protein (CC16) plasma levels are linked to accelerated lung function decline in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke–exposed (CS-exposed) Cc16(–/–) mice have exaggerated COPD-like disease associated with increased NF-κB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16(–/–) mice and whether increased NF-κB activation contributes to the exaggerated COPD in CS-exposed Cc16(–/–) lungs. CS-exposed WT and Cc16(–/–) mice were treated with recombinant human CC16 (rhCC16) or an NF-κB inhibitor versus vehicle beginning at the midpoint of the exposures. COPD-like disease and NF-κB activation were measured in the lungs. RhCC16 limited the progression of emphysema, small airway fibrosis, and chronic bronchitis-like disease in WT and Cc16(–/–) mice partly by reducing pulmonary inflammation (reducing myeloid leukocytes and/or increasing regulatory T and/or B cells) and alveolar septal cell apoptosis, reducing NF-κB activation in CS-exposed Cc16(–/–) lungs, and rescuing the reduced Foxj1 expression in CS-exposed Cc16(–/–) lungs. IMD0354 treatment reduced exaggerated lung inflammation and rescued the reduced Foxj1 expression in CS-exposed Cc16(–/–) mice. RhCC16 treatment reduced NF-κB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16(–/–) mice partly by inhibiting NF-κB activation and represents a potentially novel therapeutic approach for COPD.