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    淺析腎纖維化發病機制及研究進展

    來源:萬方期刊網  時間:2018-04-16 11:54:16  點擊:

      靜安區閘北中心醫院 腎內科

      【摘 要】目的:了解近年腎纖維化發病及治療的相關研究進展。方法:采用文獻研究方法,對近年腎纖維化的病因以及發病機制、治療方法等進行了回顧分析,提出更具治療效果的治療方法,以解決腎纖維化患者的病痛。結果:通過對各種數據文獻資料的分析研究,發現采取中西醫結合的治療方法能一定程度的阻止或減緩腎纖維化的發生,在預防腎衰上具有重要作用。結論:各種腎臟疾病都是腎纖維化的基本病理改變,最終導致終末期腎衰的發生,極大的威脅了人們的生命健康,加強對腎纖維化發病機制的研究能夠提前采取預防措施,控制使腎功能惡化的危險因素,提出阻止腎纖維化機制發生的治療措施,具有一定積極意義。

      【關鍵詞】腎纖維化;發病機制;中西醫結合

      近年,在各種對患者身體、生命造成威脅的疾病中,腎臟疾病是不得不提的一大并重,據悉每年腎臟疾病的發病率在7%以上,成為了心腦血管、腫瘤、糖尿病后的又一威脅人們健康的主要疾病。通過對各種腎臟疾病的病因研究發現,幾乎都是腎纖維化的病理改變導致,即在各種內外因素的影響下細胞外基質(ECM)過度的沉積在腎間質,造成數量的急劇增多,使得極致降解受到了抑制,最終促使腎小球硬化或小管間質纖維化的發生,也是造成腎衰的罪魁禍首之一[1]。為了采取行之有效的措施預防腎衰疾病的發生,降低死亡率,腎纖維化研究引起了醫學界的廣泛關注,并取得了不錯的進展效果,下面就將腎纖維化發病和治療機制研究結果報道如下。

      1 腎纖維化發病機制研究進程的認識

      1.1細胞因子

      隨著醫學中腎纖維化的進一步深入研究,發現細胞因子在其中發揮了很大作用,尤其是各種疾病因子致使細胞因子激增過度表達。而細胞因子誘發的腎纖維化發病機制主要表現為3方面,機慢性腎臟缺氧、機械性牽拉擠壓的張力、小管蛋白超負荷[2]。當然作為調控腎纖維化關鍵細胞因子的轉化生長因子β更是值得深入研究,它主要作用于腎小球細胞,在人的身體外就能激發腎纖維化細胞的Ⅰ、Ⅳ型膠原、纖維連接素的增多,同時還能促進纖溶酶原激活物抑制劑,也就是TIMP的合成,減少基質金屬蛋白酶MMP在人體的含量。除此之外,轉化生長因子β還能通過接收受體信號將細胞進行合成,形成抑制腎纖維化的膠原蛋白、層連粘蛋白、纖連蛋白和蛋白多糖等。白細胞介素(IL)也能通過對趨化因子的影響,讓白細胞在被感染部位快速恢復,增加金屬蛋白酶、血小板活性因子(PAF)及腫瘤壞死因子等,或是對系膜細胞產生激增刺激作用,從而導致纖維反應的發生,對腎臟功能造成一定的損害。

      1.2上皮間充質轉化(EMT)

      在腎纖維化的過程中,EMT也是一個不可獲取的關鍵過程,對器官、癌癥、腎小管間質纖維化都會產生不良影響。EMT在人體腎纖維化過程的表現為降低了細胞粘附分子的存在,甚至出現缺失的問題,而上皮標志下調、間質標志等的含量卻極度上調,從而形成成纖維細胞形態。據相關數據統計,人體近35%的成纖維細胞都來自EMT,可見它是腎纖維化發展中的一大關鍵。通常情況下,EMT以胚胎發育的形式存在,在腎小管上皮細胞對其他缺失細胞進行反應時,EMT就將發揮作用恢復失去上皮特性和功能的起源,轉變成間充質成纖維細胞,成為腎纖維化的主要機制。

      1.3血管緊張素Ⅱ——RAS系統

      RAS系統不是單一的,而是涵蓋了包括腎素、血管緊張素Ⅰ、血管緊張素原及轉換酶ACE、AngⅡ與受體等多種[3]。其中腎素以及AngⅡ大多來自近端小管上皮細胞,將其用于大鼠身上進行實驗,會看到腎小管萎縮、ECM積聚以及間質纖維化等情況的出現。當出現腎纖維化時就會刺激RAS增加AngⅡ的分泌,鑒于此通過抑制AngⅡ合成就能一定程度上減緩腎間質纖維化程度。目前替米沙坦、頡沙坦等藥物被應用在神纖維化的治療中,能有效的減少α-SMA的表達,阻斷LLC-PK1轉化成MFB的進程,效果不錯。

      1.4細胞間質

      總的來說,細胞間質涵蓋了纖維和細胞基質ECM,通過近十年的醫學研究發現致使腎組織細胞間質及合成增加了,ECM也隨之增多了。尤其是腎纖維化過程中Ⅰ、Ⅳ和Ⅲ型膠原mRNA都增多了,粘糖蛋白、蛋白聚糖PGs的含量也會發生變化,出現增加趨勢。ECM的增多沉積能促使腎小球中其構成成分改變,使得系膜基質成分增多加速腎小球內細胞的增殖,高血壓、高血糖、腎單位高濾過等都會促進腎纖維化,對人的腎臟功能造成損傷。在細胞間質增多的過程中其質降解也會減少,最突出的原因就是組織抑制因子、基質金屬蛋白酶的功能出現紊亂,這也是抑制腎纖維化的重要途徑之一。

      2 關于腎纖維化采取中西醫結合治療的研究

      在中醫中并沒有腎纖維化的說法,而是依照病癥的表現及特點,將其進行歸類為水腫、腰痛、尿血、溺毒等,致使出現這些癥狀的病機主要包括正虛和邪實,其中所謂的邪實有分為淤血、濁毒、濕濁和濕熱等,在對癥下藥進行預防治療上有一定的經驗。西醫在腎纖維化治療上的研究也不可不提,多在動物模型、體外細胞中進行臨床試驗,對未來腎纖維化的治療來說都是不可多得的手段和方法。鑒于此,將中醫和西醫進行有機結合,兩者相互取長補短,相互促進在治療腎纖維化上的效果將更為顯著。

      首先是通過食療方法來減輕腎纖維化。一般在飲食上要降低蛋白飲食的攝入,從而降低蛋白尿、TGF-β表達、膠原合成,最終達到減輕纖維化的目的。根據研究可知高血壓、高血糖、高脂血癥等都對腎纖維化具有一定的促進作用,因此在使用這些病癥的治療藥物時,應當使用ACEI、AT1受體阻滯劑、HMG-CoA還原酶抑制劑等,都能一定程度的延緩腎纖維化的作用[4]。

      其次針對ECM合成增多,過度沉積的問題,應當采取措施抑制ECM的合成,增加其降解功能。經過反復的試驗,發現干擾素-、光輝霉素、糖皮質激素等都能有效的抑制ECM的合成增多,但在具體的抗腎纖維化上作用不甚明顯。而在ECM基質降解中,激素松弛肽通過降低TIMP-1的活性,可以有效的提高間質膠原酶的活性,預防纖維化的發生。

      最后中醫通過活血化瘀、化濁排毒、清熱利濕等不同角度的研究,研發了具有一定療效的中藥。在人體外,通過服用冬蟲夏草、丹參、紅景天、川穹嗪、大黃素、滋腎止血片、黃芪、靈芝等,都能通過改變人體一些細胞,減少ECM的沉積,從而對腎纖維化產生一定的抑制、減緩作用[5]。

      3 討論

      綜上所述,腎纖維化對于人體腎功能影響巨大,很容易造成腎衰現象的出現,對人體健康和生命安全造成極大威脅。因此,通過對腎纖維化發病機制發病機制和中西醫治療方法的研究具有重要意義。

      參考文獻:

      [1]劉必成.腎臟纖維化發生機制研究進展[C].中華醫學會腎臟病學分會2010學術年會專題講座匯編,2010.

      [2]陳騰鋒,謝慶祥,張躍紅.腎臟纖維化機制的研究進展[J].國際泌尿系統雜志,2011,31(3):404-408.

      [3]張智圓,季宇彬.腎纖維化發生機制研究進展[C].第10屆全中西醫結合腎臟病學術會議論文匯編,2009:928-929.

      [4]李曠怡,張瓊.淺談腎臟纖維化的中西醫發病機理及治療研究進展[J].社區醫學雜志,2016(23):78-80.

      [5]陳鳳,戴恩來.中西醫對腎纖維化發病機制的研究進展[J].遼寧中醫雜志,2016(6):1243-1246.

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