| 摘要: | 在兒童和成人中，肥大細胞都與氣喘的發病和嚴重程度相關，並且活化的肥大細胞會釋放發炎介質和細胞激素導致趨向第二型發炎反應的產生。近年來的研究已經關注到空氣汙染對於呼吸道相關疾病的影響，並且這些空氣汙染物的懸浮粒子(例如: PM2.5和柴油引擎廢氣粒子(diesel exhausted particles, DEP))也會誘發氣道發炎、氣道過度敏感反應和氣喘的發生，但是目前對於空氣汙染粒子(如:DEP)導致氣喘發作的機制仍不清楚。在我們的研究中，我們利用過敏性和非T2氣喘病人的支氣管組織切片，以及以ovalbumin (OVA)-、air-pollutant-和DEP-challenged的BALB/c小鼠動物模式，分析氣道上皮組織切片上tryptase+的肥大細胞浸潤情形。此外，我們還使用DEP刺激human mast cells (HMC-1)以確認aryl hydrocarbon receptor (AhR)媒介肥大細胞產生警告素(alarmins)如:IL-33、IL-25和TSLP，以及IL-4、IL-5和IL-13等細胞激素合成與釋放的作用。在過敏性氣喘病人和ovalbumin-challenged小鼠，以及air-pollutant-與DEP-challenged小鼠的氣道組織切片中，皆可發現肥大細胞在上皮層的數目會增加，顯示過敏性氣喘病人更容易受到空氣汙染的刺激。當HMC-1暴露於DEP的刺激會增加IL-33、IL-25和TSLP的mRNA與蛋白質的表現，並且這些表現量會受到AhR的siRNA抑制而減少。FcεRI路徑下游活化的NF-κB p65會和AhR在細胞質結合，之後帶著AhR轉位至細胞核中並與ARNT一起結合至警告素的啟動子上。此外，DEP也會誘導HMC-1的移行作用，以及增加HMC-1對於IL-4、IL-5和IL-13的合成與釋放，並且這些現象會受到anti-ST2抗體的作用而抑制。總結來說，DEP會透過AhR/NF-κB p65路徑誘導肥大細胞產生警告素，並且由IL-33/ST2 axis導致肥大細胞增加Th2細胞激素的釋放，因而增強了過敏性氣喘中Th2媒介的氣道發炎反應。
Mast cells are involved in the pathophysiology and severity of asthma in children and adults. Inflammatory mediators and cytokines release from activated mast cells result in Th2-driven inflammation. Increasing evidences indicated environmental air pollutants have negative health impacts, particularly associated with respiratory diseases. Specific air pollutant particles can cause airway inflammation, airway hyper-responsiveness and asthma exacerbation (e.g., PM <2.5 μM in diameter (PM2.5) and diesel exhausted particles (DEP)). However, the molecular mechanisms for DEP leading to the deteriorated inflammations in asthma were still not clear. In our study, we obtained bronchial biopsies from allergic and non-T2 asthma subjects as well as ovalbumin (OVA)-, air-pollutant- and DEP-challenged mice to analyze the number of tryptase+ mast cells infiltration within airway epithelium. Moreover, cultured human mast cells (HMC-1) were stimulated with DEP to determine whether aryl hydrocarbon receptor (AhR) mediated IL-33, IL-25 and TSLP as well as IL-4, IL-5 and IL-13 synthesis and release. The number of mast cells increased in the airway epithelium of allergic asthmatics, ovalbumin -, air-pollutant- and DEP-challenged mice, suggesting allergic asthma patients were susceptible to direct exposure to air-pollutants. Human mast cells exposed to DEP up-regulated IL-33, IL-25 and TSLP at mRNA and protein levels. These effects were inhibited through knock-down of AhR by siRNA transfection. Activation of NF-κB in FcεRI-mediated pathway, the subunit p65 bound to AhR in cytosol to facilitate nuclear translocation and recruitment on promoters of alarmins. Furthermore, DEP triggered mast cells migration and increased IL-4, IL-5 and IL-13 synthesis and release, which were blocked by anti-ST2 antibodies. In conclusion, DEP stimulated AhR/NF-κB p65 pathway in mast cells to produce alarmins which mediated IL-33/ST2 axis resulting in type 2 cytokines synthesis and to enhance Th2-mediated airway inflammation in allergic asthma. |
