中藥自擬方-聖肺癒喘湯對小鼠急、慢性肺損傷模型之免疫調節研究

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题名:	中藥自擬方-聖肺癒喘湯對小鼠急、慢性肺損傷模型之免疫調節研究 The study of immunomodulatory effects of Chinese herbal medicine formula Sheng-Fei-Yu-Chuan-Tang (SFYCT) on acute and chronic lung injury murine model
作者:	林佳宏;Chia-Hung Lin
贡献者:	中醫學系博士班
关键词:	聖肺癒喘湯;內毒素;急性肺損傷;過敏性氣喘;塵?;Sheng-Fei-Yu-Chuan-Tang;acute lung injury;LPS;allergic asthma;Dermatogoides pteronyssinus
日期:	2013-07-30
上传时间:	2013-10-02 09:45:48 (UTC+8)
出版者:	中國醫藥大學
摘要:	急性肺損傷(Acute lung injury; ALI)是導致患者死亡的重要因素，降低肺臟發炎反應是對ALI患者的主要治療策略。過敏性氣喘（Allergic asthma）是一種慢性氣管發炎疾病，肇因於T淋巴細胞反應失調。本研究主旨在驗證中藥自擬方-聖肺癒喘湯，在急性與慢性肺損傷的小鼠模式中的治療效果以及免疫調節機轉。本研究分兩部分進行，第一部分：聖肺癒喘湯在小鼠急性肺損傷模式中的治療效果與免疫調節作用之研究；第二部份：聖肺癒喘湯在慢性氣喘小鼠模式中的治療效果與免疫調節作用之研究。第一部分：氣管投與LPS誘發老鼠肺部急性發炎，同時餵食聖肺癒喘湯，結果顯示：不論在肺部發炎的病理組織上、中性白血球或巨噬細胞的浸潤數量、肺部水腫指標及一氧化氮分泌的量上，皆可見到聖肺癒喘湯有減緩肺部發炎的成效。我們以ELISA 及 RT-PCR 來偵測各種發炎相關的細胞激素及趨化因子，如TNFα、IL-1β、 IL-6、MCP-1，聖肺癒喘湯皆有壓制的作用，同時我們也發現聖肺癒喘湯可誘發大量的抗發炎細胞激素IL-4和IL-10的分泌。我們利用鼠巨噬細胞RAW 264.7 進行體外研究，在western blot的結果中我們發現聖肺癒喘湯對LPS誘發產生ROS和NO有明顯抑制作用，並且降低iNOS蛋白表現，減少轉錄因子NF-κB活化現象；聖肺癒喘湯也可抑制LPS刺激所導致的A549細胞死亡現象，並且降低TNFα和MCP-1 mRNA的表現。第二部份：因為歐洲室塵?;Dermatophagoides pteronyssinus（Der p）是目前台灣造成氣喘最主要的原因之一，因此我們利用隔週連續5次氣管內接種Der p，誘導BABL/c小鼠的慢性氣喘動物模型，來探討聖肺癒喘湯治療氣喘的功效和免疫調節作用。結果顯示聖肺癒喘湯降低小鼠呼吸道過度反應(airway hyperresponsiveness )和肺部發炎細胞浸潤，並且抑制呼吸道重塑(airway remodeling)，聖肺癒喘湯也降低了Der p所誘導的氣喘小鼠血清中總IgE、Der p特異性IgG1的量，但對IgG2a/2b不影響，在這些小鼠的肺泡沖洗液中的Th2細胞激素IL-4、 IL-5和IL-13會被聖肺癒喘湯降低，肺組織中的TGF-β1和collagen分泌量也因為給予聖肺癒喘湯之後減少，Der p小鼠肺臟中的化學趨化因子Eotaxin、RANTES以及MCP-1之mRNA表現量受到聖肺癒喘湯的抑制。本研究的結論是：在急性肺損傷方面，聖肺癒喘湯可藉由降低發炎細胞激素並且提升抗發炎細胞激素達到降低肺臟發炎的效果，而此免疫調節可能是透過調控轉錄因子NF-κB 活化與否而達成。在慢性氣喘方面，聖肺癒喘湯抑制了Der p所誘導的呼吸道發炎、重塑及過度反應的現象，而這些作用與聖肺癒喘湯可能抑制Th2免疫反應、降低化學趨化因子表現，以及增加IFN-γ 與 IL-12的分泌以促進免疫系統的Th2反應轉向Th1反應有關。 Traditional Chinese medicine formula Sheng-Fei-Yu-Chuan-Tang (SFYCT), consisting of 13 medicinal plants, was used to treatment patients with lung diseases. This study investigated the immunoregulatory effect of SFYCT on intratracheal lipopolysaccharides (LPS)-challenged acute lung injury (ALI) mice and Dermatogoides pteronyssinus (Der p)-challenged chronic asthma mice. In the first part, we found that SFYCT attenuated pulmonary edema, macrophages and neutrophils inﬁltration in the airways of LPS-challenged mice. SFYCT decreased inflammatory cytokines, including tumor necrosis factor-α (TNF-??, interleukin-1β and interleukin-6, inhibited nitric oxide (NO) production, but increased anti-inﬂammatory cytokines, interleukin-4 and interleukin-10, in the bronchoalveolar lavage fluid of LPS-challenged mice. TNF-?? and monocyte chemotactic protein-1 mRNA expression in the lung of LPS-challenged mice as well as LPS-stimulated lung epithelial cell and macrophage, was decreased by SFYCT treatment. SFYCT treatment also decreased the inducible nitric oxide synthase expression and phosphorylation of nuclear factor-κB (NF-κB) in the lung of mice and macrophage with LPS stimulation. SFYCT treatment dose dependently decreased the LPS induced NO and reactive oxygen species generation in LPS-stimulated macrophage. In the second part, we demonstrated that SFYCT decreased the airway hyperresponsiveness (AHR), pulmonary inflammatory cell infiltration, and airway remodeling in Der p mice. SFYCT treatment decreased Der p-induced total IgE and Der p-specific IgG1 but not IgG2a/2b Ab titer in serum of Der p mice. SFYCT also decreased Th2 cytokines, IL-4, IL-5 and IL-13 but increased IFN-γ and IL-12 in The BALF of Der p mice. TGF-β1 and collagen production in the lung of mice were decreased by SFYCT. The mRNA expression of chemokine including Eotaxin, RANTES, and MCP-1 in the lung of Der p mice was decreased by SFYCT. In conclusion, SFYCT attenuated lung inflammation during LPS-induced ALI through decreasing inflammatory cytokines production while increasing anti-inflammatory cytokines production. The immunoregulatory effect of SFYCT during ALI is related to inhibiting NF-κB phosphorylation. On the other hand, the suppressed Der p-induced airway inflammation, remodeling and hyperresponsiveness in chronic asthma murine model are related to SFYCT inhibits Th2 responses, decrease chemokine expression and promotes IFN-γ and IL-12 production. SFYCT could skew Der p-induced Th2 responses to Th1 responses by increasing IFN-γ which is merit for clinical application on asthma patients.
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