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
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
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Research Article Immunology Inflammation

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

Abstract

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.

Authors

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

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Figure 10

Treating CS-exposed Cc16–/– mice with rhCC16 reduces NF-κB activation in their lungs, and increased NF-κB activation in the lungs of CS-exposed Cc16–/– mice contributes to their exaggerated pulmonary inflammatory response to CS.

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Treating CS-exposed Cc16–/– mice with rhCC16 reduces NF-κB activation in...
In A, WT and Cc16–/– mice were exposed to air (6 mice/group) or CS for 8 weeks (6–7 mice/group), and CS-exposed mice were treated thrice weekly with rhCC16 (75 μg of rhCC16) or vehicle. NF-κB that translocated to the nucleus was quantified in nuclear extracts of whole lung samples using a TransAM NF-κB kit. In B, NF-κB luciferase reporter A549 cells were grown to at least 80% confluence and preincubated for 3 hours with 100 μg/mL of rhCC16. Cells were then activated with rhTNF-α (1–10 ng/mL), and 8 hours later, the cells were lysed and luciferase activity was measured. In C, WT and Cc16–/– mice were exposed to air (3–5 mice/group) or CS for 12 weeks (10–12 mice/group), and CS-exposed mice were treated once daily with a solution of IMD0354 (6 mg/kg body weight) or vehicle via the intraperitoneal route during the last 6 weeks of the CS exposures (5–6 mice/group). BAL was performed, and BAL total leukocytes (C), macrophages (D), and PMNs (E) were counted. Boxes in the box plots show the medians and 25th and 75th percentiles, and whiskers show the 10th and 90th percentiles. Data were analyzed using 1-way ANOVAs followed by pairwise testing with Mann-Whitney U tests. In A and C–E, asterisks indicate P < 0.05 vs. air-exposed mice belonging to the same genotype or the group indicated; in B, asterisks indicate P < 0.05 vs. negative control in lane 1 or the group indicated.