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)：BMI与成人哮喘患者循环CC16水平降低显著且单调相关。此外，CC16与痰中嗜酸性粒细胞和血液中的骨膜蛋白呈负相关。在五年的随访中，血清CC16水平最低三分位数的患者的FEV1值比最高三分位数的患者下降了-14.3mL(趋势=0.031)。2)动物实验：肥胖小鼠小气道CC16-细胞百分率降低。此外，肥胖小鼠的血清CC16水平显著低于非肥胖对照组小鼠。然而，肥胖和非肥胖对照组小鼠之间的血清SP-A和SP-D水平没有变化，这些都是俱乐部细胞的其他产物。3)北海道出生队列：对一般人群10岁儿童进行循环CC16测定。7岁和10岁时的BMI与10岁时CC16降低有关。有喘息者的血浆CC16(中位数5.2，IQR 3.8-6.1)显著低于无喘息者(中位数5.6，IQR 4.3-7.1)。血浆CC16水平与喘息和哮喘的患病率呈负相关，CC16浓度每增加1 ng/ml，学龄儿童发生喘息的风险降低20%(校正优势比：0.80，95%CI：0.66~0.99)。此外，CC16与T2表型、局部(FeNO)和全身性炎症(血嗜酸性粒细胞)呈负相关。目前，我们关注的是尿液氧化和脂质过氧化与CC16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.