Golder Mark, Burleigh David E, Belai Abi, Ghali Lucy, Ashby Deborah, Lunniss Peter J, Navsaria Harry A, Williams Norman S
Academic Department of Surgery, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
Lancet. 2003 Jun 7;361(9373):1945-51. doi: 10.1016/S0140-6736(03)13583-0.
Evidence from clinical and laboratory investigations into the causes of diverticular disease suggests that disturbances in cholinergic activity are important, the effector mechanisms of which have yet to be established. We aimed to investigate the role of smooth muscle and neural cholinergic activity in the pathogenesis of this disease.
Two investigators independently did a blinded immunohistochemical image analysis of localising antibodies to choline acetyltransferase, co-localised with protein gene product (PGP)--a marker of general neural tissue-and smooth muscle muscarinic M3 receptors, on three histological sections of sigmoid colons from ten patients with diverticular disease and ten controls, after resections for rectal tumours. We also did isotonic organ bath experiments to assess muscle strip sensitivities to exogenous acetylcholine.
In circular muscle, activity of choline acetyltransferase was lower in patients with diverticular disease than in controls: median percentage surface area of choline acetyltransferase over PGP was 17.5% (range 10.0-37.0) in patients with diverticular disease and 47.0% (29.0-54.0) in controls (p<0.0001). M3 receptors were upregulated in patients with diverticular disease compared with controls: the median surface area was 13.2% (6.0-23.3) in patients with diverticular disease and 2.5% (1.6-3.7) in controls (p<0.0001). The sensitivity to exogenous acetylcholine was increased in patients with diverticular disease (mean -log EC(50) 5.6 [SD 0.3]) compared with controls (4.9 [0.5]; difference 0.7 [95% CI 0.3-1.1], p=0.006). In longitudinal muscle, choline acetyltransferase activity was lower in patients with diverticular disease (median 19.5%, range 12.0-30.0) than in controls (47.0%, 35.0-60.0; p<0.0001), with upregulation of M3 receptors in diverticular disease (diverticular disease 7.8% [1.9-20.4], controls 1.7% [0.8-3.0]; p<0.0001). However, sensitivity to exogenous acetylcholine did not differ between the two groups (diverticular disease mean 5.6% [SD 0.3], controls 5.2% [0.4]; difference 0.4% [95% CI -0.02-0.7], p=0.06).
Our results suggest that cholinergic denervation hypersensitivity can affect smooth muscle. Upregulation of smooth muscle M3 receptors might account for specific clinical, physiological, and pharmacological abnormalities associated with diverticular disease.
临床和实验室对憩室病病因的调查证据表明，胆碱能活性紊乱很重要，但其效应机制尚未明确。我们旨在研究平滑肌和神经胆碱能活性在该疾病发病机制中的作用。
两名研究者对来自10例憩室病患者和10例对照者（因直肠肿瘤切除术后）的乙状结肠的三个组织学切片，独立进行了胆碱乙酰转移酶定位抗体的盲法免疫组化图像分析，该抗体与蛋白质基因产物（PGP，一种一般神经组织的标志物）以及平滑肌毒蕈碱M3受体共定位。我们还进行了等张器官浴实验，以评估肌条对外源性乙酰胆碱的敏感性。
在环行肌中，憩室病患者的胆碱乙酰转移酶活性低于对照者：憩室病患者胆碱乙酰转移酶在PGP上的中位表面积百分比为17.5%（范围10.0 - 37.0），对照者为47.0%（29.0 - 54.0）（p<0.0001）。与对照者相比，憩室病患者的M3受体上调：憩室病患者的中位表面积为13.2%（6.0 - 23.3），对照者为2.5%（1.6 - 3.7）（p<0.0001）。与对照者（4.9 [0.5]）相比，憩室病患者对外源性乙酰胆碱的敏感性增加（平均-log EC(50) 5.6 [标准差0.3]）；差异为0.7 [95%置信区间0.3 - 1.1]，p = 0.006。在纵行肌中，憩室病患者的胆碱乙酰转移酶活性低于对照者（中位值19.5%，范围12.0 - 30.0）（对照者为47.0%，35.0 - 60.0；p<0.0001），憩室病中M3受体上调（憩室病7.8% [1.9 - 20.4]，对照者1.7% [0.8 - 3.0]；p<0.0001）。然而，两组对外源性乙酰胆碱的敏感性无差异（憩室病平均5.6% [标准差0.3]，对照者5.2% [0.4]；差异0.4% [95%置信区间 - 0.02 - 0.7]，p = 0.06）。
我们的结果表明，胆碱能去神经超敏反应可影响平滑肌。平滑肌M3受体上调可能是与憩室病相关的特定临床、生理和药理学异常的原因。
