Inflammatory bowel disease (IBD) arises from a dysregulated mucosal immune response to luminal bacteria. Toll-like receptor (TLR)4 recognizes LPS and transduces a proinflammatory signal through the adapter molecule myeloid differentiation marker 88 (MyD88). We hypothesized that TLR4 participates in the innate immune response to luminal bacteria and the development of colitis. TLR4-/- and MyD88-/- mice and littermate controls were given 2.5% dextran sodium sulfate (DSS) for 5 or 7 days followed by a 7-day recovery. Colitis was assessed by weight loss, rectal bleeding, and histopathology. Immunostaining was performed for macrophage markers, chemokine expression, and cell proliferation markers. DSS treatment of TLR4-/- mice was associated with striking reduction in acute inflammatory cells compared with wild-type mice despite similar degrees of epithelial injury. TLR4-/- mice experienced earlier and more severe bleeding than control mice. Similar results were seen with MyD88-/- mice, suggesting that this is the dominant downstream pathway. Mesenteric lymph nodes from TLR4-/- and MyD88-/- mice more frequently grew gram-negative bacteria. Altered neutrophil recruitment was due to diminished macrophage inflammatory protein-2 expression by lamina propria macrophages in TLR4-/- and MyD88-/- mice. The similarity in crypt epithelial damage between TLR4-/- or MyD88-/- and wild-type mice was seen despite decreased epithelial proliferation in knockout mice. TLR4 through the adapter molecule MyD88 is important in intestinal response to injury and in limiting bacterial translocation. Despite the diversity of luminal bacteria, other TLRs do not substitute for the role of TLR4 in this acute colitis model. A defective innate immune response may result in diminished bacterial clearance and ultimately dysregulated response to normal flora.

BACKGROUND AND AIMS: Considerable difficulties persist amongst pathologists in agreeing on the presence and severity of gastric atrophy. An international group of pathologists pursued the following aims: (i) to generate an acceptable definition and a simple reproducible classification of gastric atrophy; and (ii) to develop guidelines for the recognition of atrophy useful for increasing agreement among observers.\ud \ud METHODS: After redefining atrophy as the 'loss of appropriate glands' and examining histological samples from different gastric compartments, three categories were identified: (i) negative; (ii) indefinite; (iii) atrophy, with and without intestinalization. Atrophy was graded on a three-level scale. Interobserver reproducibility of the classification was tested by kappa statistics (general and weighted) in a series of 48 cases.\ud \ud RESULTS: The medians of the general agreement and weighted kappa values were 0.78 and 0.73, respectively. The weighted kappa coefficients, obtained by cross-tabulating the evaluation of each pathologist against all others, were, with only one exception, > 0.4 (moderate to excellent agreement).\ud \ud CONCLUSIONS: By using the definition of atrophy as the loss of appropriate glands and distinguishing the two main morphological entities of metaplastic and non-metaplastic types, a high level of agreement was achieved by a group of gastrointestinal pathologists trained in different cultural contexts

Cell proliferation and apoptosis in kidneys with chronic obstructive uropathy (COU) have not been adequately studied. Whether these fundamental cellular processes play any role in the pathogenesis and evolution of COU remains undetermined. Sprague-Dawley rats with COU induced by unilateral ureteral ligation were sacrificed at postoperative days 1, 6, 9, 15, 34, 43, 60, 75, and 90, and were compared with control, sham-operated rats sacrificed at days 0, 15, 43, and 90. The kidneys with ureteral ligation, the contralateral kidneys, and the control kidneys were submitted to in situ end-labeling of fragmented DNAs for the detection of apoptotic cells, and to immunostaining with many monoclonal antibodies directed against the nuclear antigens associated with cell proliferation for the detection of proliferating cells. Additional rats with COU were also submitted to BrdU labeling to detect proliferating cells. The tubular, interstitial, and glomerular cells showing either apoptosis or proliferation were separately quantitated and the obtained data were correlated with dry kidney weight, tubular diameter, glomerular surface area and interstitial volume. Apoptotic tubular cells in kidney with COU increased rapidly, reaching 30-fold that of control at day 25, which was followed by an equally rapid decrease to the control level. During the same period, both the dry kidney weight and the mean tubular diameter decreased markedly. These data suggest that apoptosis may play a significant role in tubular atrophy and renal weight loss. The rapid increase in tubular cell apoptosis was immediately preceded by a 37% gain in the dry kidney weight over the control; just before that increase, there was also an approximate 60-fold increase in the proliferation rate of tubular cells detected by immunostaining for proliferating nuclear antigen or by BrdU labeling. The significance of this intriguing temporal relationship of tubular cell apoptosis and proliferation remains to be elucidated, but it may have pathogenetic implications. In contrast to the rise and fall of the frequency of tubular cell apoptosis and proliferation, the frequency of interstitial cell apoptosis and proliferation displayed continuous increase toward the end of the experiment, with a roughly parallel increase in the interstitial damage. Apoptosis and proliferation of glomerular cells in kidneys with COU did not show any significant changes throughout the experiment. In conclusion, the obtained data suggest that tubular cell apoptosis may be pathogenetically related to the tubular atrophy and renal tissue loss in COU, and that proliferation and apoptosis of interstitial cells may play a role in the observed interstitial changes in this model. This study should provide the impetus for further exploration of the mechanisms of cell death and cell proliferation as a novel venue for understanding the pathogenesis of COU.

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