Potential role of club cell secretory protein (CC16) in development of obese asthma: findings from a birth cohort and animal studies

1)成人哮喘队列）：在成人哮喘患者中，BMI与循环CC 16水平降低显著且单调相关。此外，CC 16与痰嗜酸性粒细胞和血骨膜蛋白呈负相关。基线时血清CC 16水平最低三分位数的患者在5年随访期间的FEV 1比最高三分位数的患者下降了-14.3 mL（趋势p = 0.031）。2)动物研究：肥胖小鼠小气道中CC 16-细胞的百分比降低。此外，肥胖小鼠的血清CC 16水平显著低于非肥胖对照小鼠。然而，SP-A和SP-D的血清水平，俱乐部细胞的其他产品，没有肥胖和非肥胖对照小鼠之间的变化。3)北海道出生队列：我们测量了一般人群中10岁儿童的循环CC 16。7岁和10岁时的BMI与10岁时CC 16降低相关。与无喘息的儿童（中位数5.6，IQR 4.3-7.1）相比，喘息儿童的血浆CC 16（中位数5.2，IQR 3.8-6.1）显著较低。血浆CC 16与喘息和哮喘患病率呈负相关，CC 16增加1 ng/mL可使学龄儿童喘息风险降低20%（校正比值比：0.80，95% CI：0.66-0.99）。此外，CC 16与T2表型和局部（FeNO）和全身炎症（血液嗜酸性粒细胞）呈负相关。目前，我们的研究重点是尿氧化和脂质过氧化与CC 16和肥胖哮喘表型的关系。

1) Adult asthma cohort): BMI was significantly and monotonously associated with reduced circulating CC16 levels in adult asthmas patients. Also, CC16 was inversely associated with sputum eosinophils and blood periostin. Patients with the lowest tertile of serum CC16 levels at baseline had a -14.3 mL decline in FEV1 than those with the highest tertile over five years of follow-up (p for trend = 0.031). 2) Animal study: The percentage of CC16-cells was reduced in the small airways of mice with obesity. In addition, serum CC16 levels were significantly lower in obese mice than in non-obese control mice. However, the serum levels of SP-A and SP-D, other products of club cells, did not vary between obese and non-obese control mice. 3) Hokkaido birth cohort: We measured circulatory CC16 in 10 year-old children of general population. BMI at age 7 and 10 was associated with reduced CC16 at age 10. Children with wheeze had a significant lower plasma CC16 (median 5.2, IQR 3.8-6.1) compared to children without wheeze (median 5.6, IQR 4.3-7.1). Plasma CC16 was inversely associated with wheeze and asthma prevalence, and 1 ng/mL increase in CC16 decreases 20% risk of wheeze in school age children (adjusted odds ratio: 0.80, 95% CI: 0.66-0.99). Also, CC16 is inversely associated with T2 phenotypes and local (FeNO) and systemic inflammation (blood eosinophils). Currently, we are focusing on the association of urinary oxidative and lipid peroxidation with CC16 and obese asthma phenotype.