嚴重呼吸症候群是一種新興疾病，起因為SARS病毒的感染。患者在發病後期常會併發非典型肺炎，導致患者急性的嚴重肺部創傷，或進一步導致肺部纖維化的發生。由於此疾病死亡率高（10~15%），且在爆發其間造成許多國家的醫療與經濟損失，因此了解此疾病的致病機轉，進一步提供醫療對策，實為當務之急。本實驗室之前分析來自台灣疾病管制局88位SARS病人血清檢體中的細胞激素表現，感染急性期有干擾素-g相關激素風暴的現象 。除此以外，相關的臨床證據也看到，通常疾病發作一星期後病毒量都已降低，顯示不正常的免疫反應在此疾病中扮演著重要的角色。 因此我們利用體外的系統探討，是否一些病人中高量表現的細胞激素可能造成肺部表皮細胞的死亡，或是肺部纖維母細胞不正常的活化—代表體外系統看纖維化發生的指標。由於 IFN-g及TGFb1這兩種細胞激素，都可在SARS病人中有不正常的高量表現，且都可能影響肺部表皮細胞的細胞凋亡，或肺部纖維母細胞的活化，因此我們進一步了解當兩種細胞激素共同存在時，是否有相互拮抗或協同的作用，影響肺部表皮細胞或纖維母細胞的命運。以A549肺部表皮細胞為模型，觀察到IFN-g可藉由提升細胞表面Fas的表現量，而使細胞對Fas傳遞的細胞凋亡訊息更敏感。若將細胞以 IFN-g培養一段時間先提升Fas表現，再給予Fas訊息的話，則可觀測到表皮細胞大量凋亡。而TGFb1可以降低細胞表現Fas的量，抵消 IFN-g提升細胞對Fas所調控凋亡作用的敏感性。然而在纖維母細胞方面，我們以HFL-1細胞株為模型，可看到此兩種細胞激素對Fas表現量的調控與表皮細胞相同，但Fas的表現與否似乎不太影響細胞對Fas傳遞細胞凋亡訊息的敏感性。但若以a-型平滑肌蛋白（a-smooth muscle actin）的表現量作為細胞分化的指標，可看到 IFN-g或 Fas訊息都可降低其表現量， 但 TGFb1可抵消 IFN-g及Fas訊息的抑制作用。細胞先以 IFN-g培養一段時間，可看到 TGFb1增進纖維母細胞a-型平滑肌蛋白表現的情形被Fas訊息所抑制。總括而言，我們觀察到 IFN-g及TGFb1在肺部表皮細胞及纖維母細胞上都可調節Fas的表現量，且扮演著相互拮抗的角色。而Fas訊息的活化可引發肺部表皮細胞凋亡，同時抑制肺部纖維母細胞的活化。根據這些試管內的結果，我們認為 IFN-g及 TGFb1參與SARS肺部病變，可能經由下列方式：在SARS的早期病毒引發大量的 IFN-g及免疫細胞的浸潤，使我們相信應該免疫細胞的Fas ligand提供細胞Fas的訊息。 IFN-g增強Fas的表現，使表皮細胞經由細胞凋亡造成傷害， TGFb1雖然可減緩此現象，但卻效用有限。 IFN-g也可藉由提升纖維母細胞Fas 的表現量，使纖維母細胞經由Fas 的訊息抑制細胞活化， 在疾病後期，浸潤細胞減少，也使Fas的抑制作用減緩， TGFb1的表現量仍高， 纖維母細胞持續受到活化，可能造成纖維化。

　　Severe acute respiratory syndrome (SARS) is a new emerging disease caused by SARS-associated coronavirus (SARS-CoV). After infection, patients may develop acute lung injury, which sometimes progresses to pulmonary fibrosis. Analysis of SARS patients’ early stage and convalescent sera revealed the presence of a IFN-g related cytokine storm. This observation, together with the description of persistent acute lung injury after a drop in viral load, suggests that pulmonary damage in SARS patients may be the result of an immunopathological effect. Many reports indicate that IFN-g and TGFb1, which were detected in SARS patients’ sera, could mediate epithelial apoptosis or fibroblast activation. Thus we are interested in the effect of these two cytokines on lung epithelial or fibroblast and how they interact by antagonism or synergism. We found that IFN-g could enhance Fas-mediated apoptosis in A549 lung epithelial cells through the increase of the Fas expression. On the contrary, TGFb1 could partially block IFN-g-enhanced Fas-mediated apoptosis through the decrease of the Fas expression. The effect of these two cytokines on the Fas expression of the HFL-1 human lung fibroblasts were similiar, but without affecting the sensitivity to Fas-mediated apoptosis. Furthemore, IFN-g and Fas activation could downregulate a–smooth muscle actin (a fibroblast differentiation and activation marker) expression, but TGFb1 could counteract this effect. Fibroblasts after priming with IFN-g became more sensitive to Fas-mediated a-smooth muscle actin inhibition. We conclude that IFN-g and TGFb1 could antagonisticly regulate Fas expression in both human lung epithelial cells and fibroblasts, and indirectly regulate Fas-mediated apoptosis or a–smooth muscle actin expression. In SARS, the immune cells that infiltrate to the lungs after SARS-CoV infection may provide a source of Fas ligand. The dominant IFN-g expression could cause lung epithelial cells damage through Fas-mediated apoptosis. TGFb1 could counteract this effect in a different extent. However, in the late stage as Fas ligand expression and IFN-g level decreased, TGFb1 would enhance the fibroblast activation. Together with the damaged epithelial cells, pulmonary fibrosis might develop.

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