空氣污染物對肺部發炎及過敏疾病之影響

背景：研究已證實空氣污染物對過敏性疾病患者的有害影響，細顆粒物（PM2.5）是一種常見的主要空氣污染物，其與肺功能下降密切相關，可誘發過敏性氣道炎症，並與慢性肺部疾病存在顯著關聯。另外，血管生成素樣蛋白4（ANGPTL4）是一種具有多重功能的細胞因子，參與炎症、血管生成及轉移等病理過程。薑黃素是從薑黃植物中提取的活性化合物，具有抗氧化、抗炎、抗癌及免疫調節等多種藥理作用。方法：各別進行基礎實驗室及臨床研究基礎研究雙重目的：首先探究PM2.5暴露下ANGPTL4在肺部炎症和癌變中的作用，其次闡明薑黃素對ANGPTL4表達的影響及其在肺癌化學預防中的潛力。臨床研究：2007至2011年間，從臺灣臺中市某醫院招募225名6至15歲的過敏性鼻炎（AR）兒童，並根據其對塵?（如屋塵?、熱帶無爪?或微角塵?）的敏感度進行分類。評估「兒童鼻結膜炎生活質量問卷（PRQLQ）」分數、過敏原特異性免疫球蛋白E水平與空氣污染水平之間的相關性。流行病學研究：從國家數據庫中匹配9868名AR兒童的記錄（研究年份、年齡及城市與臨床研究一致），分析AR門診就診率、局部AR藥物處方量與空氣污染物水平的關聯。污染物包括二氧化硫（SO?）、一氧化碳（CO）、臭氧（O?）、直徑<10微米（PM??）及<2.5微米（PM?.?）的懸浮微粒、一氧化氮（NO）、二氧化氮（NO?）、非甲烷碳氫化合物（NMHC）及甲烷（CH?）。結果：實驗室研究中我們採用蛋白質晶片檢測多種促發炎細胞激素因子，隨後通過qPCR驗證發現：隨著PM2.5濃度升高，CXCL1、CXCL5、IL-1α、IL-1β、MIP-3α等發炎反應/纖維化相關蛋白表達顯著增強。薑黃素可抑制PM2.5誘導的ANGPTL4表達及IκB-α（NFκB抑制劑）依賴性訊息傳遞路徑。通過shRNA降低基因表現量ANGPTL4能恢復IκB-α的表達，且能改善PM2.5所誘導CXCL5、IL-1α、IL-1β、MIP-3α等炎症/纖維化相關蛋白表達的增加。流行病學研究：CO、NO、NO?和CH?水平與男孩的局部AR藥物處方量顯著相關，而女孩僅CH?有顯著關聯。臨床研究：PRQLQ分數與空氣污染物的正相關性僅見於男孩，女孩無此現象。校正干擾因素後，CO、PM?.?和NO?水平僅與對熱帶無爪?（Bt）敏感的男孩顯著相關，而對其他?類敏感的兒童則無此關聯。結論：實驗室研究結果表明，支氣管上皮細胞經PM2.5處理後ANGPTL4表達上調，促進肺部IκB-α（NFκB抑制劑）依賴性炎症進展的作用機制之一。本研究證實，薑黃素作為抗炎治療劑可成為具有潛益的化學預防藥物。AR男孩對空氣污染物比女孩更敏感，且對Bt敏感的AR男孩比其他?敏感者及所有女孩更易受空氣污染物影響。

Background: Research has confirmed the harmful effects of air pollutants on patients with allergic diseases. Fine particulate matter (PM2.5), a common and major air pollutant, is closely associated with decreased lung function, can trigger allergic airway inflammation, and is significantly linked to chronic lung diseases. In addition, angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine involved in pathological processes such as inflammation, angiogenesis, and metastasis. Curcumin, an active compound extracted from the turmeric plant, possesses various pharmacological properties, including antioxidant, anti-inflammatory, anticancer, and immunomodulatory effects.Methods: Basic laboratory and clinical studies were conducted separately.Basic Research – Dual Objectives:First, to investigate the role of ANGPTL4 in lung inflammation and carcinogenesis under PM2.5 exposure; second, to elucidate the effect of curcumin on ANGPTL4 expression and its potential in lung cancer chemoprevention.Clinical Study:Between 2007 and 2011, a total of 225 children aged 6 to 15 years with allergic rhinitis (AR) were recruited from a hospital in Taichung City, Taiwan. They were classified based on their sensitivity to dust mites (e.g., Dermatophagoides pteronyssinus, Dermatophagoides farinae, or Blomia tropicalis). The study assessed the correlation among Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) scores, allergen-specific immunoglobulin E (IgE) levels, and air pollution levels.Epidemiological Study:Records of 9,868 children with AR were retrieved from a national database, matched by study year, age, and city to the clinical study. The analysis explored the relationship between air pollutant levels and both AR outpatient visit rates and the prescription volume of local AR medications. Pollutants analyzed included sulfur dioxide (SO?), carbon monoxide (CO), ozone (O?), particulate matter with diameters less than 10 micrometers (PM??) and 2.5 micrometers (PM?.?), nitric oxide (NO), nitrogen dioxide (NO?), non-methane hydrocarbons (NMHC), and methane (CH?).Results:In the laboratory study, we used a protein microarray to detect various pro-inflammatory cytokines. Subsequent qPCR validation revealed that with increasing concentrations of PM2.5, the expression of inflammation/fibrosis-related proteins such as CXCL1, CXCL5, IL-1α, IL-1β, and MIP-3α was significantly elevated.Curcumin was found to inhibit PM2.5-induced ANGPTL4 expression and suppress the IκB-α-dependent (an NFκB inhibitor) inflammatory pathway. Silencing ANGPTL4 using shRNA restored the expression of IκB-α and MIP-3α.Epidemiological Study:Levels of CO, NO, NO?, and CH? were significantly associated with the prescription volume of local allergic rhinitis (AR) medications in boys, while in girls, only CH? showed a significant association.Clinical Study:A positive correlation between PRQLQ scores and air pollutant levels was observed only in boys, with no such pattern seen in girls. After adjusting for confounding factors, levels of CO, PM?.?, and NO? were significantly associated only with boys who were sensitive to Blomia tropicalis (Bt), and not with children sensitive to other types of mites.Conclusion:The laboratory findings suggest that the upregulation of ANGPTL4 expression in lung cells following PM2.5 exposure may be one of the mechanisms by which PM2.5 promotes the progression of lung inflammation. This study confirms that curcumin, as an anti-inflammatory agent, holds potential as a chemopreventive drug.Boys with allergic rhinitis (AR) are more sensitive to air pollutants than girls, and among them, those sensitized to Blomia tropicalis (Bt) are more affected by air pollution compared to boys sensitized to other mites and all girls.