Interstitial cells of Cajal (ICC) are implicated in the regulation of gut peristalsis and are immunostained by antibodies against Kit (CD117), a tyrosine kinase receptor. Most gastrointestinal mesenchymal tumors (GIMTs) are of uncertain histogenesis, although many are CD34-positive. CD34 was found to colocalize with vimentin (Vim) and the Kit-positive networks of cells within and around neural plexi, indicating that ICC can be Vim- and CD34-positive. ICCs appear to be the only Kit+CD34+Vim+ cell in the gut. Formalin-fixed, paraffin-embedded tissues from 43 GIMTs were immunostained for Kit, CD34, Vim, PGP 9.5 (PGP, a neural marker), muscle-specific actin (MSA), and other markers including desmin (Des). Eight tumors were myoid (MSA+Des+Vim-Kit-CD34-), and one was a schwannoma (PGP+S100+Vim+Kit-CD34-), but 34 tumors were of uncertain histogenesis (gastrointestinal stromal tumors, GIST), exhibiting neither a complete myoid nor a schwannian immunophenotype. All 34 were Vim+, and 33/34 were either Kit (n = 30) or CD34 (n = 23) immunoreactive. Of these 34 GIST, 24 were negative for all myoid and neural markers, 6 were PGP+S100-, and 4 were MSA+Des-. The Kit+CD34+Vim+ immunophenotype of GIST suggests that they originate from, or have differentiated into, ICC-like cells; the term ICC tumor (ICCT) is suggested. Kit is a more sensitive marker than CD34 for ICCT, but both are required in tumor identification. All clinically malignant GISTs were pathologically malignant (size, mitoses) but also showed loss of either CD34 or Kit. "Blind" examination of electron micrographs in 10 tumors showed them to be heterogeneous. Some had features seen in normal ICC, but cells could not be positively identified as being adult ICC. GIMT may therefore be classifiable into those with pure myoid, schwannian (or neural) differentiation, but the majority are of ICC origin or show ICC differentiation immunophenotypically (ICCT).

Tumor necrosis factor-alpha is up-regulated in a variety of different human immune-inflammatory and fibrotic pulmonary pathologies. However, its precise role in these pathologies and, in particular, the mechanism(s) by which it may induce fibrogenesis are not yet elucidated. Using a replication-deficient adenovirus to transfer the cDNA of tumor necrosis factor-alpha to rat lung, we have been able to study the effect of transient but prolonged (7 to 10 days) overexpression of tumor necrosis factor-alpha in normal adult pulmonary tissue. We have demonstrated that local overexpression resulted in severe pulmonary inflammation with significant increases in neutrophils, macrophages, and lymphocytes and, to a lesser extent, eosinophils, with a peak at day 7. By day 14, the inflammatory cell accumulation had declined, and fibrogenesis became evident, with fibroblast accumulation and deposition of extracellular matrix proteins. Fibrotic changes were patchy but persisted to beyond day 64. To elucidate the mechanism underlying this fibrogenesis, we examined bronchoalveolar fluids for the presence of the fibrogenic cytokine transforming growth factor-beta1 and tissues for induction of alpha-smooth muscle actin-rich myofibroblasts. Transforming growth factor-beta1 was transiently elevated from day 7 (peak at day 14) immediately preceding the onset of fibrogenesis. Furthermore, there was a striking accumulation of myofibroblasts from day 7, with the most extensive and intense immunostaining at day 14, ie, coincident with the up-regulation of transforming growth factor-beta1 and onset of fibrogenesis. Thus, we have provided a model of tumor necrosis factor-alpha-mediated pulmonary inflammation and fibrosis in normal adult lung, and we suggest that the fibrogenesis may be mediated by the secondary up-regulation of transforming growth factor-beta1 and induction of pulmonary myofibroblasts.

Most gastrointestinal stromal tumors (GISTs),The hypothesis that gastrointestinal stromal tumors (GISTs) originate from interstitial cells of Cajal (ICC) is currently disputed 1 and the controversy was highlighted by a recent editorial in the Journal Laboratory Investigation.2 GISTs are nonepithelial mesenchymal neoplasms that arise in the wall of the gastrointestinal tract, which are commonly CD34 immunoreactive but usually lack markers for true leiomyomas and schwannomas. [3][4][5][6][7][8] The hypothesis that GISTs originate from ICC was initiated after the observation that almost all GISTs were double positive for the Kit membrane tyrosine kinase receptor (CD117) and CD34, and that ICC were the only cells in the gut which were double positive for Kit and CD34 as determined by immunohistochemistry. 5,9 ICC are mesenchymal cells in origin, and are located within the gut wall between most neural plexi and smooth muscle cells. Networks of ICC are associated with Auerbach's plexus and with the deep muscular plexus (small intestine) and submuscular plexus (colon). ICC are also found within the muscle layers of the gut wall. Some of these ICC networks participate in the generation of the pacemaker activity of the gut 10 -12 involved in the generation of peristaltic motor activity, 13 others may participate in neurotransmission.14 ICC have been shown to be Kit-positive by immunohistochemistry, [15][16][17] in situ hybridization, 18 and single-cell polymerase chain reaction (PCR).11 Whether or not ICC express CD34 is currently debated, because some authors report CD34 immunoreactivity, 5,9,19 whereas others do not find such expression in ICC.1 This debate is important for weighing evidence for and against the hypothesis that GISTs arise from or differentiates toward ICC. ICC within the stomach and small and large intestine were found to be double positive for Kit and CD34 using immunohistochemistry and confocal laser-scanning microscopy.9 Kindblom et al 5 identified a small subset of Kit-positive cells within the myenteric plexus of the human gastrointestinal tract that were also CD34-positive. In another study using double-fluorescence immunostaining of the external muscle layers of the human stomach and colon, most of the Kit immunoreactive cells were also positive for CD34, but some ICC-like cells were positive for CD34 and negative for Kit, and some kit-positive cells

Crohn's disease (CD) is a chronic, relapsing inflammatory bowel disease, characterized by transmural inflammation. In CD, the recurrent inflammatory injury and tissue repair that occurs in the intestine can progress uncontrollably, leading to the proliferation of mesenchymal cells as well as fibrosis, characterized by excessive extracellular matrix deposition. These processes thicken the bowel wall, reducing flexibility, and often culminate in obstructive strictures. Because no effective measures are currently available to specifically treat or prevent intestinal stricturing, we sought to gain a better understanding of its pathogenesis by developing a mouse model of intestinal fibrosis. Because transforming growth factor (TGF)-beta1 can mediate both fibrosis and mesenchymal cell proliferation; we studied the effects of delivering adenoviral vectors encoding spontaneously active TGF-beta1 into the colons of mice. We first demonstrated that enema delivery of marker adenoviral vectors led to the transfection of the colonic epithelium and transient transgene expression. Histologically, control vectors caused an acute inflammatory response, involving the recruitment of neutrophils and mononuclear cells into the colonic lamina propria; however, infection caused little if any fibrosis. In contrast, the TGF-beta1 vector caused a more severe and prolonged inflammatory response as well as localized collagen deposition, leading to severe and progressive fibrosis. This was accompanied by the emergence of cells with a myofibroblast phenotype. Ultimately the fibrosis resulted in many of the TGF-beta1-transfected mice developing profound colonic obstruction. Through adenoviral gene transfer technology, we describe a novel mouse model of colitis and implicate TGF-beta1 in the pathogenesis of obstructive intestinal fibrosis.

Gut 2003;52:966-970 Delayed gastric emptying can be due to muscular, neural, or humoral abnormalities. In the absence of an identified cause, gastroparesis is labelled as idiopathic. We present the case of a patient with severe idiopathic gastroparesis. Pharmacological approaches failed, as well as reduction in gastric emptying resistance with pyloric injection of botulinum toxin and pyloroplasty. Therefore, subtotal gastrectomy was performed. Histological and immunohistochemical study of the resected specimen showed hypoganglionosis, neuronal dysplasia, and a marked reduction in both myenteric and intramuscular interstitial cells of Cajal. To our knowledge, this is the first time these rare histological findings have been described in a patient with idiopathic gastroparesis. U nderstanding of both normal and abnormal gastrointestinal function has gained momentum in recent decades. However, gastric motility and, in particular, the relative contribution of all of the factors involved in the coordination of food propulsion are still poorly understood. Gastric emptying reflects the integration of tonic contractions of the proximal stomach (fundic tone), phasic contractions of the antrum, and the inhibitory forces of pyloric and duodenal contractions. These complex phenomena require cooperation between smooth muscle, enteric and autonomic nerves, and interstitial cells of Cajal (ICC).