Abstract

Background:

Exposure to wood smoke (WS) increases the risk for chronic bronchitis more than exposure to cigarette smoke (CS), but the underlying mechanisms are unclear.

Objective:

The effect of WS and CS on mucous cell hyperplasia in mice and in human primary airway epithelial cells (AECs) was compared with replicate the findings in human cohorts. Responsible WS constituents were identified to better delineate the pathway involved, and the role of a tumor protein p53 (Tp53) gene polymorphism was investigated.

Methods:

Mice and primary human AECs were exposed to WS or CS and the signaling receptor and pathway were identified using short hairpin structures, small molecule inhibitors, and Western analyses. Mass spectrometric analysis was used to identify active WS constituents. The role of a gene variant in Tp53 that modifies proline to arginine was examined using nasal brushings from study participants in the Lovelace Smokers Cohort, primary human AECs, and mice with a modified Tp53 gene.

Results:

WS at 25-fold lower concentration than CS increased mucin expression more efficiently in mice and in human AECs in a p53 pathway-dependent manner. Study participants who were homozygous for p53 arginine compared with the proline variant showed higher mucin 5AC (MUC5AC) mRNA levels in nasal brushings if they reported WS exposure. The WS constituent, oxalate, increased MUC5AC levels similar to the whole WS extract, especially in primary human AECs homozygous for p53 arginine, and in mice with a modified Tp53 gene. Further, the anion exchange protein, SLC26A9, when reduced, enhanced WS- and oxalate-induced mucin expression.

Discussion:

The potency of WS compared with CS in inducing mucin expression may explain the increased risk for chronic bronchitis in participants exposed to WS. Identification of the responsible compounds could help estimate the risk of pollutants in causing chronic bronchitis in susceptible individuals and provide strategies to improve management of lung diseases. https://doi.org/10.1289/EHP9446

中文翻译：

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木烟成分对小鼠和人气道上皮细胞粘蛋白基因表达的影响，以及对 Tp53 易感基因变异受试者的鼻上皮细胞的影响

摘要

背景：

接触木烟 (WS) 比接触香烟烟雾 (CS) 更能增加慢性支气管炎的风险，但其潜在机制尚不清楚。

客观的：

将 WS 和 CS 对小鼠和人类原代气道上皮细胞 (AEC) 粘液细胞增生的影响与在人类队列中复制的发现进行了比较。确定了负责任的 WS 成分以更好地描绘所涉及的途径，并研究了肿瘤蛋白 p53 ( Tp53 ) 基因多态性的作用。

方法：

小鼠和原代人类 AEC 暴露于 WS 或 CS，并使用短发夹结构、小分子抑制剂和 Western 分析鉴定信号受体和通路。质谱分析用于识别活性 WS 成分。Tp53 中将脯氨酸修饰为精氨酸的基因变异的作用通过来自 Lovelace 吸烟者队列、主要人类 AEC 和具有修饰Tp53基因的小鼠的研究参与者的鼻刷检查。

结果：

浓度比 CS 低 25 倍的 WS 以 p53 通路依赖性方式更有效地增加了小鼠和人类 AEC 中的粘蛋白表达。与脯氨酸变体相比，p53 精氨酸纯合子的研究参与者如果报告 WS 暴露，则在刷鼻时表现出更高的粘蛋白 5AC (MUC5AC) mRNA 水平。WS 成分草酸盐增加了类似于整个 WS 提取物的 MUC5AC 水平，尤其是在 p53 精氨酸纯合的原代人类 AEC 中，以及在具有修饰的Tp53基因的小鼠中。此外，阴离子交换蛋白 SLC26A9 在减少时会增强 WS 和草酸盐诱导的粘蛋白表达。

讨论：

与 CS 相比，WS 在诱导粘蛋白表达方面的效力可能解释了暴露于 WS 的参与者患慢性支气管炎的风险增加。鉴定负责的化合物可以帮助估计污染物在易感个体中引起慢性支气管炎的风险，并提供改善肺部疾病管理的策略。https://doi.org/10.1289/EHP9446