趙玉璽++閆磊++閆躍飛++皇超英++李亞昆++薛永康++趙新芳++張震
摘要:闡述了犢牛分泌性腹瀉形成機(jī)制、分類及治療方法,以期促進(jìn)新藥物的開發(fā)和犢牛養(yǎng)殖行業(yè)的健康發(fā)展。
關(guān)鍵詞:犢牛;分泌性腹瀉;治療方法;研究進(jìn)展
中圖分類號(hào):S858.23 文獻(xiàn)標(biāo)識(shí)碼:B 文章編號(hào):1007-273X(2017)08-0010-03
幼犢期疾病對(duì)養(yǎng)牛業(yè)的經(jīng)濟(jì)產(chǎn)生重大影響,犢牛的損失、治療的直接成本、生產(chǎn)性能降低等[1]。犢牛腹瀉是一種常見的疾病,也是造成奶牛經(jīng)濟(jì)損失的主要原因。分泌性腹瀉是犢牛腹瀉的一種類型,了解分泌性腹瀉的形成機(jī)理對(duì)于犢牛腹瀉的防治十分必要。
1 分泌性腹瀉形成的機(jī)制
腹瀉是由于腸上皮細(xì)胞分泌過多或吸收的液體和電解質(zhì)受損造成的。流體在腸腔和血液流動(dòng)是由離子的主動(dòng)運(yùn)輸驅(qū)動(dòng)的,主要是Na+、Cl-、HCO3-、K+和溶質(zhì)(主要是葡萄糖)。液體吸收或分泌涉及位于頂端(面向管腔)和基底(面向循環(huán))上皮細(xì)胞膜膜轉(zhuǎn)運(yùn)蛋白的協(xié)調(diào)[2]。腸上皮細(xì)胞結(jié)構(gòu)由手指狀突起(絨毛)和腺狀的管狀結(jié)構(gòu)(隱窩)組成,相對(duì)絨毛和腺窩比例不同。在功能上,吸收和分泌可以發(fā)生在相同的上皮細(xì)胞,隱窩在分泌過程占主導(dǎo)地位,絨毛在吸收過程占主導(dǎo)地位。
液體吸收的主要驅(qū)動(dòng)力來自于跨腸上皮細(xì)胞Na+的主動(dòng)運(yùn)輸和Cl-或者HCO3-的吸收。這個(gè)過程的電化學(xué)驅(qū)動(dòng)力來自于基底外側(cè)的Na+/K+-ATP酶。在小腸中液體的吸收是在Na+/H+轉(zhuǎn)運(yùn)蛋白3(NHE3,又叫做SLC9A3)、Na+/葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白1(SLC5A1)和Cl-/HCO3-轉(zhuǎn)換器[DRA(SLC26A3)和PAT1(SLC26A6)]作用下完成的[3]。電中性液體的吸收是在NHE3和Cl-/HCO3-轉(zhuǎn)換器協(xié)同活化作用下完成(PAT1主要影響HCO3-的吸收,而DRA主要影響空腸和結(jié)腸對(duì)Cl-的吸收)[4]。基質(zhì)特異性轉(zhuǎn)運(yùn)蛋白(如SLC5A1)促進(jìn)Na+與D-葡萄糖(或半乳糖)一起跨越頂膜,電中性葡萄糖轉(zhuǎn)運(yùn)蛋白SLC2A2促進(jìn)葡萄糖離開基底外側(cè)膜[5]。在近端結(jié)腸Na+的轉(zhuǎn)運(yùn)除了Na+/H+轉(zhuǎn)運(yùn)蛋白,還可與通過Na+通道轉(zhuǎn)運(yùn)和短鏈脂肪酸的轉(zhuǎn)運(yùn)來協(xié)同轉(zhuǎn)運(yùn)。胞內(nèi)信使包括Ca2+和環(huán)化核苷酸,例如cAMP和cGMP可以抑制細(xì)胞膜頂端的Na+轉(zhuǎn)運(yùn)蛋白的活性[6],從而抑制液體的吸收。
腸液分泌是通過基底外側(cè)和頂端Cl-通道和轉(zhuǎn)運(yùn)蛋白的跨上皮分泌物驅(qū)動(dòng)的。Cl-通過由Na+/K+-ATP酶產(chǎn)生的Na+濃度梯度驅(qū)動(dòng)的Na/K/Cl轉(zhuǎn)運(yùn)體(NKCC1,也稱為SLC12A2)在基底外側(cè)膜轉(zhuǎn)運(yùn)到細(xì)胞中[7]?;淄鈧?cè)K+通道(KCNQ1/KNE3和KCNN4)提供了跨過Cl-通道的頂端Cl-離子的電化學(xué)驅(qū)動(dòng)力[8],這一過程主要是環(huán)核苷酸激活的囊性纖維化跨膜傳導(dǎo)調(diào)節(jié)子(CFTR)和Ca2+活化了Cl-通道。腸神經(jīng)和細(xì)胞表面受體如鈣敏感受體(CaSR)也被認(rèn)為可調(diào)節(jié)細(xì)胞內(nèi)信號(hào)通路,從而調(diào)節(jié)電解質(zhì)的吸收和分泌[9]。
2 分類
2.1 細(xì)菌性腹瀉
細(xì)菌,如霍亂弧菌和腸毒素性大腸桿菌分泌特異性腸毒素(分別為霍亂毒素和熱穩(wěn)定腸毒素),增加細(xì)胞內(nèi)環(huán)核苷酸的水平,導(dǎo)致頂端CFTR Cl-通道的活化,因此引起腸液分泌[10]。來自永生化和原代人腸細(xì)胞的數(shù)據(jù)顯示,細(xì)菌腸毒素的cAMP、cGMP和Ca2+濃度的升高也抑制NHE3[11]。細(xì)菌也可以增加各種體液激動(dòng)劑,神經(jīng)遞質(zhì)或神經(jīng)肽受體例如5羥色胺,VIP肽和1型甘藍(lán)素受體,從而激活Cl-分泌并抑制Na+吸收[12]。侵入性細(xì)菌如沙門氏菌和志賀氏菌引起組織炎癥反應(yīng),包括免疫細(xì)胞的聚集和細(xì)胞因子的釋放,導(dǎo)致細(xì)胞內(nèi)Ca2+發(fā)生信號(hào)傳導(dǎo)[13]。致腸病侵襲性的細(xì)菌也導(dǎo)致運(yùn)輸?shù)鞍妆磉_(dá)的改變,引起腹瀉。
2.2 病毒性腹瀉
輪狀病毒感染腸道后會(huì)引起液體的分泌和小腸上皮細(xì)胞結(jié)構(gòu)的改變,產(chǎn)生與年齡相關(guān)的分泌性腹瀉[14]。復(fù)雜的輪狀病毒蛋白(NSP4)被認(rèn)為是通過結(jié)合膜受體(整聯(lián)蛋白α1β2),神經(jīng)肽甘丙肽或通過腸神經(jīng)激活引起細(xì)胞質(zhì)Ca2+濃度升高的腸毒素[15]。輪狀病毒NSP4還抑制NHE3和SLC5A1[16]。目前尚不知道其他腸道病毒,例如諾如病毒引起腹瀉的分子機(jī)制[17]。可能存在藥物誘導(dǎo)腹瀉的多種致病機(jī)制,但有證據(jù)表明某些藥物,例如化療藥物通過類似于輪狀病毒性腹瀉的細(xì)胞內(nèi)Ca2+依賴機(jī)制誘導(dǎo)腹瀉[18]。
2.3 炎性腹瀉
自身免疫性疾病,如犢牛乳糜瀉可見腸道炎癥。雖然這些疾病的主要特征是繼發(fā)于不適當(dāng)?shù)拿庖呒?xì)胞活化的慢性組織損傷,但幾種重疊的信號(hào)傳導(dǎo)途徑影響腸液輸送穩(wěn)態(tài)[19]。激活上皮炎癥信號(hào)通路如NF-κB導(dǎo)致Ca2+或環(huán)狀核苷酸信號(hào)傳導(dǎo)和刺激分泌或抑制Na+吸收。通過激活的T細(xì)胞和嗜中性粒細(xì)胞釋放炎癥介質(zhì)如TNF和IL-6,導(dǎo)致黏膜肥大細(xì)胞脫顆粒、組胺、前列腺素的釋放也可以刺激分泌[20]。也可能通過炎癥影響上皮Na+吸收,主要是因?yàn)橐恍┘?xì)菌病原體,如艱難梭菌,這是導(dǎo)致抗生素相關(guān)性腹瀉的最常見原因。艱難梭菌相關(guān)性腹瀉和結(jié)腸炎發(fā)生是繼發(fā)性的,可以激活上皮細(xì)胞炎癥信號(hào)通路并招募免疫細(xì)胞。
3 治療方法
3.1 口服補(bǔ)液法
動(dòng)物腹瀉口服補(bǔ)液治療方法是從人治療霍亂的基礎(chǔ)上發(fā)展而來的,口服補(bǔ)液治療腹瀉被認(rèn)為是20世紀(jì)醫(yī)學(xué)最重要的進(jìn)步[21]。有效的口服補(bǔ)液一般要求溶液易被吸收、能補(bǔ)充細(xì)胞外液量、糾正酸中毒[22]。
在選擇口服補(bǔ)液藥物時(shí)需要考慮以下因素。由于Na+是細(xì)胞外液滲透壓的主要離子,所以在選擇的藥物應(yīng)該含有Na+。研究發(fā)現(xiàn),Na+濃度為120 mmol/L的溶液糾正了脫水,而濃度較低的溶液則沒有[23]。較少的研究表明,溶液中Na+的濃度>130 mmol/L是有害的。獸醫(yī)師一般建議口服補(bǔ)液的藥物Na+的濃度在90~130 mmol/L[24]。促進(jìn)口服補(bǔ)液治療發(fā)展的關(guān)鍵科學(xué)是發(fā)現(xiàn)鈉和葡萄糖的偶聯(lián)轉(zhuǎn)運(yùn)[25]。除了葡萄糖外,中性氨基酸(例如甘氨酸或谷氨酰胺)和揮發(fā)性脂肪酸(如乙酸鹽或丙酸鹽)已被證明能增強(qiáng)腸內(nèi)鈉的吸收[26]。葡萄糖與鈉比例為1~3∶1在獸醫(yī)臨床上已被推薦。endprint
代謝性酸中毒被認(rèn)為是新生犢牛腹瀉頻繁且潛在的嚴(yán)重并發(fā)癥。腹瀉導(dǎo)致更少的碳酸氫鹽通過糞便排出體外,減少腎小球?qū)潆x子的濾過率,L-乳酸在犢牛體內(nèi)的積累,導(dǎo)致更為嚴(yán)重的酸中毒。除此之外,反芻動(dòng)物產(chǎn)生和吸收D-乳酸在犢牛代謝性酸中毒中也起到重要的作用[27]。代謝性酸中毒在反芻動(dòng)物幼年期比其他動(dòng)物更為常見[28],這很可能是目前關(guān)于犢牛使用口服補(bǔ)液藥物的堿化能力的建議(60-80毫克/升[29])遠(yuǎn)高于當(dāng)前WHO推薦的(30 mmol/L)[30],通常用于商業(yè)口服補(bǔ)液的碳酸氫鹽和碳酸氫鹽前體主要是乙酸鹽和丙酸鹽。碳酸氫鹽使酸酐比丙酸鹽和乙酸鹽更高程度地酸化,從而降低小??辜?xì)菌感染的非特異性抗性[31]。在喂奶后不到2~4 h,避免使用含碳酸氫鹽的口服補(bǔ)液藥物。
3.2 持續(xù)飼喂法
傳統(tǒng)上無論是短時(shí)間腹瀉還是持續(xù)性腹瀉,首先被推薦的是取消犢牛牛奶喂養(yǎng)[32]。但是沒有足夠的科學(xué)證據(jù)能證明饑餓可以提高腹瀉犢牛的治愈率。事實(shí)上,盡管在腹瀉期間犢牛消化能力有所降低,但是,喂奶不會(huì)惡化或延長腹瀉的過程。相反,取消牛奶供應(yīng)會(huì)迅速導(dǎo)致營養(yǎng)不良和體重下降[33]。持續(xù)喂奶不僅提供了整個(gè)腹瀉期間增重和增長所需的能量,而且提供了恢復(fù)腸黏膜所必需的營養(yǎng)[34]。
3.3 適當(dāng)?shù)氖褂每股?/p>
獸醫(yī)行業(yè)也面臨著使用抗生素日趨嚴(yán)峻的壓力,濫用抗生素可促進(jìn)抗生素耐藥菌株的選擇和隨后的增殖[35]。在這種情況下,Constable[35]對(duì)新生小牛腹瀉中抗菌素治療的益處進(jìn)行了研究,得出以下結(jié)論:不推薦在沒有系統(tǒng)疾病的犢牛中使用口服或注射用抗生素;腹瀉和全身疾病的犢牛(顯著的抑郁癥、厭食、發(fā)熱),有細(xì)菌血癥或敗血病風(fēng)險(xiǎn)以及小腸細(xì)菌過度生長的風(fēng)險(xiǎn)時(shí),推薦使用廣譜β-內(nèi)酰胺抗菌藥(頭孢噻呋,阿莫西林或氨芐青霉素),強(qiáng)化磺胺類或氟喹諾酮類;從糞便樣本培養(yǎng)的細(xì)菌敏感性測試不能可靠地預(yù)測腹瀉犢牛的治療結(jié)果。
3.4 輔助治療用藥
使用美洛昔康的非甾體抗炎藥物治療已被證明在改善腹瀉犢牛的食物攝入和體重增加方面是有效的,氟尼辛葡甲胺在治療由熱穩(wěn)定大腸桿菌腸毒素引起犢牛便血有比較好的效果。過去有人使用糖皮質(zhì)激素、運(yùn)動(dòng)性調(diào)節(jié)劑來治療犢牛腹瀉,現(xiàn)該治療方法已被禁止,也有人使用腸道保護(hù)劑和益生菌來治療腹瀉,但沒有科學(xué)證據(jù)證明它們確實(shí)有效[36]。
4 小結(jié)
分泌性腹瀉(細(xì)菌、病毒、炎性)是引起犢牛腹瀉的常見病因。明白分泌性腹瀉的致病機(jī)理、常用的治療方法以及犢牛腹瀉治療的誤區(qū),在治療腹瀉犢牛時(shí)選擇合理的藥物和合理的方法,提高腹瀉犢牛治愈率,減輕奶農(nóng)負(fù)擔(dān),促進(jìn)中國奶牛養(yǎng)殖健康發(fā)展。
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