氣道重塑於氣喘之機轉及治療

Mechanism and Treatment of Airway Remodeling

郭志熙(Chih-His Kuo) ； 熊得志(Te-Chih Hsiung) ； 黃建達(Chien-Da Huang) ； 郭漢彬(Han-Pin Kuo)

《內科學誌》 20卷2期 (2009/04) Pp. 129-138

https://doi.org/10.6314/JIMT.2009.20(2).04

摘要

上皮脫落、杯狀細胞及黏膜下腺體增生、上皮下纖維化、細胞外間質沉積、以及氣道平滑肌肥大增生，支氣管血管新生，是氣喘病患氣道重塑(airway remodeling)的主要特徵。由於這些病理變化導致氣道壁厚度增加，進而產生不可逆(irreversible)的氣流限制和氣道過度敏感。在氣喘病患的氣道中，纖維母細胞(fibroblasts)或肌纖維母細胞(myofibroblasts)被認爲經由TGF-beta1 (transforming growth factor-beta1)爲主的細胞激素之刺激，改變了MMP-9 (matrix metalloproteinase -9)與TIMP-1 (tissue inhibitor of matrix metalloproteinase-1)的平衡，而促進了細胞外間質沉積。近來研究也發現，骨髓生成的纖維球(fibrocytes)扮演了纖維母細胞或肌纖維母細胞的前驅細胞(progenitor cells)角色，在特定細胞激素的引導下，由血流循環中移行(migration)至發炎的氣道。透過網狀複雜的機轉，因過敏性氣管發炎而產生的許多細胞激素，共同參與了氣道重塑的過程。另外，呼吸道平滑肌除了是一種被動的調節支氣管運動張力的組織外，在疾病狀況下如氣喘，呼吸道平滑肌進行顯著的表形變化，扮演調節氣道發炎與重塑的角色。基於許多氣喘病程與氣道重塑程度之不對稱，以及對類固醇治療之抗藥性，近期出現更多的關注在氣道重塑與氣管發炎是同時平行發生的新思維，一旦形成氣道重塑，則肺功能會出現不可逆之阻塞性變化。在當前，對新診斷的氣喘病患，早期使用吸入性類固醇治療，仍是防止其產生氣道重塑最有效的方法。最近，較新型的吸入性類固醇因具備超細微粒，例如hydrofluoroalkane (HFA)-ciclesonide，因而較能到達周邊型氣道和肺組織，較有效針對周邊型氣道的發炎和氣道重塑治療。白三烯素(leukotriene) C4及D4 被認爲在纖維母細胞增生和細胞外間質的產生扮演一個重要角色，因此，白三烯素受體拮抗劑在影響氣道重塑的作用上值得更進一步地研究。另外，在一些老鼠氣喘模型的實驗中指出，上皮生長因子受器酥胺基酸激酶(epidermal growth factor receptor [EGFR] tyrosine kinase)與血管內皮生長因子(vascular endothelial growth factor，VEGF)也有可能成爲一個未來的治療標的。

關鍵字

氣喘 ； 氣道重塑 ； 纖維球 ； 呼吸道平滑肌 ； 吸入性類固醇

並列摘要

Airway remodeling is a consequence of asthmatic airway inflammation characterized by submucosal gland hyperplasia, subepithelial fibrosis, extracellular matrix deposition, smooth muscle hypertrophy and submucosal angiogenesis. The remodeled asthmatic airway contributes to the irreversible flow obstruction and bronchial hyper-responsiveness. Activated fibroblasts and myofibrolasts alter the balance of MMP-9 (matrix metalloproteinase -9) and TIMP-1 (tissue inhibitor of matrix metalloproteinase-1) through the stimulation of TGFbeta1 (transforming growth factor-beta1), therefore, promotes the extracellular matrix deposition. Bone marrow derived fibrocytes migrate to the asthmatic airway from blood circulation acts as a progenitor cell of fibroblast and myofibrolast. Chemokines and cytokines implicated in the fibrocytes recruitment orchestrate the complex network of asthmatic inflammation, thereafter, strengthen the asthmatic airway remodeling. Airway smooth muscle which is traditionally known to be a controller of the airway tone, also exhibits phenotype alteration during asthmatic inflammation, and mediates the progression of airway remodeling. Based on the finding that severity of airway remodeling sometimes disproportionate to the history of asthma, a new insight of the asthma points out the parallel contribution of airway remodeling and asthmatic inflammation. Currently, inhaled corticosteroid is the standard treatment of asthma, and the early administration of inhaled corticosteroid is the most effective strategy to prevent airway remodeling. Hydrofluoroalkane (HFA)-ciclesonide, a newer inhaled corticosteroid with fine particles which exhibits good lung deposition, effectively suppresses the asthmatic small airway inflammation. Leukotriene C4 and D4 which are recently known to mediate the fibroblast proliferation and extracellular matrix deposition, poses leukotriene antagonist a reasonable choice for further investigation of airway remodeling therapy. Furthermore, based on the finding of murine asthmatic models, epidermal growth factor receptor tyrosine kinase and vascular endothelial growth factor are the future therapeutic targets of asthmatic airway remodeling.

並列關鍵字

Asthma ； Airway remodeling ； Fibrocyte ； Airway smooth muscle ； Inhaled corticosteroid