Sensory nerves appear to have a protective effect against acute injury in the gastric mucosa. Their function in the intestine is unclear.
In this study an immune-complex model of colitis was used to ...induce inflammation in the distal colon with and without functional ablation of sensory neurons by capsaicin pretreatment.
Colitis was more severe in the capsaicin-pretreated group than in the vehicle group 48 and 96 hours after induction of colitis. Neutrophil infiltration, expressed as inflammatory index, was significantly increased to 4.25 +/- 0.4 vs. 1.83 +/- 0.5 at 48 hours and to 2.66 +/- 0.6 vs. 1.65 +/- 0.3 at 96 hours in the capsaicin group and the vehicle group, respectively. The microscopic ulcer index also was significantly increased in the capsaicin-pretreated group compared with the vehicle group (63.3 +/- 10.6 vs. 3.3 +/- 2.4 at 48 hours, 20.0 +/- 8.4 vs. 1.5 +/- 1.1 at 96 hours). Immunoreactive substance P (SP) and calcitonin gene-related peptide (CGRP) contents were decreased in extracts of inflamed compared with uninflamed colon.
These data suggest that sensory neurons have a protective role in an acute rabbit model of experimental colitis by release of sensory neuropeptides (SP, CGRP), which may modulate vascular tone and mucosal blood flow.
Pronounced changes in gut neuropeptide content have been observed in colonic tissues from animals with acute experimental colitis and in some patients with inflammatory bowel disease. The early ...decrease of CGRP in the colon during colitis in the animal studies suggest that CGRP is released during the inflammatory process. No data are available showing the biological action of released CGRP during inflammation. The sensory neurotoxin capsaicin was used in animal studies to examine the effect of sensory nerves on inflammation and healing in experimental animal models. The severity of colitis was enhanced after capsaicin pretreatment in acute and chronic animal models of colitis. These data support the hypothesis that sensory nerves exert a protective and healing-promoting function in the gut. CGRP is a good candidate for this action of sensory nerves because it is a major component in sensory nerve fibers. How CGRP exerts its protective function in the intestine is unknown. Data from gastric ulcer models support the hypothesis that a main action of CGRP is regulation of mesenteric and mucosal blood flow resulting in enhanced protection and tissue healing. Other effector roles of CGRP afferent nerve endings could also be considered.
Diabetic nephropathy is a leading cause of end-stage renal disease. Recently, there have been developments in understanding the role of risk factors and pathogenetic features such as genetic ...predisposition, systemic and intraglomerular hypertension, the effects of glycemic control, glomerular hypertrophy, and basic biochemical alterations in cellular metabolism, as well as correlations in morphology and function. These are reflected in newer approaches to preventive and palliative therapy.
To determine the nephron segment distribution of tubular epithelial damage and regeneration and the proliferative activity of various nephron segments in human acute tubular necrosis (ATN) with an ...antibody to proliferating cell nuclear antigen (PCNA) and to compare the findings in native kidneys with ATN with those in transplant kidneys with ATN, archival tissues from 12 native and 21 transplant kidney biopsy specimens and nine transplant nephrectomy specimens were collected that all showed obvious morphological signs of ATN. Nineteen patients with transplant kidneys with ATN were immunosuppressed with cyclosporine and 11 were immunosuppressed with prednisone and azathioprine. There was a predominance of “regenerating” tubules (tubules with thin epithelium) in the distal nephron in native kidneys with ATN; in the transplant kidneys this was less conspicuous. The number of Tamm-Horsfall protein (THP)-positive tubules was decreased in all kidneys with ATN compared with normal human kidneys. In contrast, the number of THP-positive casts was much higher in all kidneys with ATN than in the normal kidneys. In transplant kidneys with ATN the number of THP-positive casts was substantially lower than in native kidneys with ATN. The macula densa appears to maintain its morphological integrity in kidneys with ATN. Both regenerating and normal appearing tubules expressed vimentin and HLA-DR. The proliferation index (PI; ie, percentage of PCNApositive nuclei) of the renal tubular epithelium in normal control kidneys varied between 0.22 and 0.33, depending on the tubule segment. The highest PI was noted in the transplant kidneys with ATN not treated with cyclosporine (8.0), followed by the native kidneys with ATN (4.4) and the transplant kidneys with ATN treated with cyclosporine (4.3). We did not find any significant difference in the PI between the regenerating (5.0) and normal appearing (5.6) tubules. Proximal tubules (8.7) showed significantly higher PI values than distal tubules (3.5) in transplant kidneys with ATN. Our results show substantial differences between native kidneys and transplant kidneys with ATN. Tubular epithelial cell proliferation in human ATN is prominent and appears to correlate with the severity of ATN. Light microscopically normal appearing tubules and regenerating tubules participate equally in the regeneration of injured tubules. Cyclosporine may have an inhibitory effect on cell regeneration (proliferation) in human transplant kidneys with ATN.
Apoptosis in mesangial cells induced by ionizing radiation and cytotoxic drugs. Mesangial proliferation contributes to the pathogenesis of many forms of glomerulonephritis. To evaluate the role of ...apoptosis on the pharmacologic effects of cytotoxic drugs and ionizing radiation, we studied their effects on cultured rat mesangial cells (MC), whose apoptotic response to these drugs is unknown. Mesangial cells were cultured with or without stimuli to induce apoptosis and were harvested at 24 and 48 hours. MC morphology was examined by light microscopy, in situ end labeling technique using terminal deoxy-transferase (TUNEL) and by electrophoresis of extracted total cellular DNA. MCs exposed to cytotoxic drugs or irradiation demonstrated statistically significant increases in apoptotic cells identified by light microscopy. DNA fragmentation of apoptotic cells was also visualized as characteristic staining by the TUNEL method and statistically significant increases in apoptotic cell number in cells exposed to cytotoxic drugs and irradiation were noted compared to control cultures. In general, the number of TUNEL positive cells was greater than that of morphologically apoptotic cells. DNA extracted from these cells also showed the characteristic ladder pattern of internucleosomal chromatin cleavage of 180bp fragments on agarose gel electrophoresis. To further analyze whether MC apoptosis induced by these drugs alters the cell cycle, 3H-thymidine incorporation rates were measured in both the cell culture monolayer and in those cells shed into the supernatant when cultured with or without cyclophosphamide (N = 5). 3H-thymidine incorporation corrected for total cellular DNA showed a similar pattern in both control and cyclophosphamide treated groups, suggesting that cyclophosphamide did not alter the mesangial cell cycle. Considering that the dosage of the cytotoxic drugs utilized in these experiments is nearly the therapeutic plasma level in humans, these results suggest that cytotoxic drugs used to treat glomerular disease can induce apoptotic mesangial cell death and may operate in part via this mechanism.
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