JCI Insight (Mar 2023)

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

  • Joselyn Rojas-Quintero,
  • Maria Eugenia Laucho-Contreras,
  • Xiaoyun Wang,
  • Quynh-Anh Fucci,
  • Patrick R. Burkett,
  • Se-Jin Kim,
  • Duo Zhang,
  • Yohannes Tesfaigzi,
  • Yuhong Li,
  • Abhiram R. Bhashyam,
  • Zhang Li,
  • Haider Khamas,
  • Bartolome Celli,
  • Aprile L. Pilon,
  • Francesca Polverino,
  • Caroline A. Owen

Journal volume & issue
Vol. 8, no. 6

Abstract

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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.

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