Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whereas T lymphocytes are essential for the initiation of acute graft-versus-host disease (aGVHD), it is not at all clear whether they or other cells or noncellular factors actually mediate the characteristic lesions. This report describes the in vivo effects of human NK cells, T cells, and cytokines on the induction of aGVHD in 4 Gy sublethally irradiated C.B-17 scid/scid (SCID) mice. Human NK and T lymphocytes were obtained separately by antibody- and complement-mediated negative selection from the peripheral blood of normal donors and expanded in medium containing rIL-2 and irradiated autologous feeder cells. The characteristics of the two groups of cells were analyzed before injection into SCID mice. Cytofluorometric phenotyping demonstrated that 70-95% of NK-enriched cells expressed CD3-, CD16+, CD56+, and CD8-dim+; ninety-seven per cent of T cells expressed CD3+, TCR-alpha/beta+, CD4+, or CD8-bright+. Analysis of K562 and Daudi cultured target cell lines demonstrated 40-50% higher cytotoxicity by NK-enriched cells as compared with activated T lymphocytes. TNF-alpha cytokine production was greatly increased in activated NK cells (250 pg/ml) as compared with T cells (25 pg/ml) and fresh PBMC (12.5 pg/ml). IFN-gamma was increased in both NK and T cells. After i.v. injection of 1-5 x 10(7) cells into irradiated SCID mice, minor to severe skin lesions, diarrhea, and weight loss occurred in NK- but not the T cell-injected animals. In NK-injected animals, thinning and focal loss of epithelium with pyknotic nuclear change and degeneration and loss of skin appendages were observed. Single cell necrosis, crypt abscess formation, and loss of glandular epithelium developed in the colon of NK but not in T cell-injected animals. These findings are very similar to allogeneic aGVHD in SCID mice injected with C57BL/6 mouse splenocytes. Immunohistological staining with anti-human CD56, CD3, TNF-alpha, and IFN-gamma antibodies demonstrated CD56+ cells in association with TNF-alpha and IFN-gamma secretion in the bowel of NK-injected animals. CD3+ cells were not found in the same tissues. These findings were not observed in T cell-injected and control mice. In summary, aGVHD-like lesions were induced by transplantation of xenogeneic human activated NK cells into SCID mice. We hypothesize that cytokines released from human NK cells play a central role in the pathogenesis of clinical aGVHD.
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PMID:Acute graft-versus-host-like disease induced by transplantation of human activated natural killer cells into SCID mice. 835 98

Gnotobiotic mice inoculated with an enterohemorrhagic Escherichia coli (EHEC) O157:H7 strain developed a flaccid paresis, usually culminating in death. The bacteria colonized feces at 10(9) to 10(10) CFU per g (inoculum size: 2.0 x 10(9) CFU/mouse), and Shiga-like toxins (SLTs) were detected in the feces. A microscopic examination of colons showed mild inflammatory cell infiltration, thinning of the intestinal wall, or necrotic foci. Necrosis of tubular cells was noted in these symptomatic mice. Microhemorrhage, thrombosis, and edematous changes of the brain were also seen. Inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin 1alpha (IL-1alpha), and IL-6, were detected in the kidney after EHEC infection, but not in the serum. In the brain, only TNF-alpha was detected. When 2.0 x 10(2) CFU of EHEC O157:H7 was fed to germ-free mice, the number of bacteria began to rise rapidly on day 1 and was maintained at 10(8)to 10(9) CFU/g of feces. SLTs were detected in the feces of the mice. However, the mice showed no histological changes and no cytokine responses, similar to what was found for controls. Treatment with TNF-alpha modified the clinical neural signs, histopathological changes, and cytokine responses; mice treated with TNF-alpha developed severe neurotoxic symptoms and had higher frequencies of systemic symptoms and glomerular pathology. Strong cytokine responses were seen in the kidney and brain. Serum cytokines were also detected in this group. In contrast, a TNF-alpha inhibitor (protease inhibitor) inhibited these responses, especially in the brain. However, local synthesis of the cytokines was observed in the kidney. Thus, TNF-alpha and the other proinflammatory cytokines could be important in modifying the disease caused by EHEC.
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PMID:Role of tumor necrosis factor alpha in gnotobiotic mice infected with an Escherichia coli O157:H7 strain. 942 58

Previous studies in the canine heart had shown that the growth of collateral arteries occurs via proliferative enlargement of pre-existing arteriolar connections (arteriogenesis). In the present study, we investigated the ultrastructure and molecular histology of growing and remodeling collateral arteries that develop after femoral artery occlusion in rabbits as a function of time from 2 h to 240 days after occlusion. Pre-existent arteriolar collaterals had a diameter of about 50 microm. They consisted of one to two layers of smooth muscle cells (SMCs) and were morphologically indistinguishable from normal arterioles. The stages of arteriogenesis consisted of arteriolar thinning, followed by transformation of SMCs from the contractile- into the proliferative- and synthetic phenotype. Endothelial cells (ECs) and SMCs proliferated, and SMCs migrated and formed a neo-intima. Intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) showed early upregulation in ECs, which was accompanied by accumulation of blood-derived macrophages. Mitosis of ECs and SMCs started about 24 h after occlusion, whereas adhesion molecule expression and monocyte adhesion occurred as early as 12 h after occlusion, suggesting a role of monocytes in vascular cell proliferation. Treatment of rabbits with the pro-inflammatory cytokine MCP-1 increased monocyte adhesion and accelerated vascular remodeling. In vitro shear-stress experiments in cultured ECs revealed an increased phosphorylation of the focal contacts after 30 min and induction of ICAM-1 and VCAM-1 expression between 2 h and 6 h after shear onset, suggesting that shear stress may be the initiating event. We conclude that the process of arteriogenesis, which leads to the positive remodeling of an arteriole into an artery up to 12 times its original size, can be modified by modulators of inflammation.
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PMID:Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis). 1078 85

We have maintained a transgenic mouse model of hydrocephalus created to overproduce the cytokine, transforming growth factor-beta1 (TGF-beta1) in the central nervous system (CNS). The aim of the present study was to estimate the embryonic period when the transgenic mice would develop hydrocephalus, by investigating the chronological developmental changes of the cerebral ventricles. Qualitative analysis of ventricular size was performed on sections cut in the coronal plane of embryos at the 15th (E15) and 18th (E18) embryonic days, and postnatal mice aged 4 days (P4). The presence of the TGF-beta1 transgene was determined by performing polymerase chain reaction (PCR) analysis. We have examined 24 embryos and 14 postnatal mice. By performing PCR analysis, the TGF-beta1 transgene was determined to be present in 16 (42.1%). Five of 16 embryos at E15 carried the transgene, and showed a slight enlargement of the lateral ventricles. Three of 8 embryos at E18 carried the transgene, and had remarkable enlargement of the lateral ventricles. Eight of 14 pups at P4 carried the transgene, and 7 of 8 pups with the transgene developed hydrocephalus. In pups that were positive for the transgene, massive enlargement of the lateral ventricles was observed and there was an associated thinning of the overlying cerebral cortex. These results suggest that congenital hydrocephalus may develop at an important embryonic time period, which coincides with the stage of neural stem cell proliferation and differentiation in the CNS.
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PMID:Chronologic changes of cerebral ventricular size in a transgenic model of hydrocephalus. 1112 34

Common variable immunodeficiency (CVI) is characterized by a failure in B-cell differentiation and impaired immunoglobulin secretion, but with a variable clinical presentation, including the development of sarcoidal granulomas and autoimmune diseases, as well as an increased incidence of malignancies. We present a 21-year-old white man who carried a diagnosis of juvenile rheumatoid arthritis and presented 6 years later with scarring alopecia showing sarcoidal granulomas. Further work confirmed the diagnosis of CVI, and with increasing systemic symptoms, it was elected to treat the patient with a tumour necrosis factor (TNF)-alpha antagonist, a TNF-alpha receptor IgG1 fusion protein. The patient showed improvement in his systemic symptoms and some hair regrowth after 3 months of therapy, and continued improvement in his systemic disease with only mild scalp hair thinning in the areas of prior involvement after almost 1 year of therapy. CVI and sarcoid may have overlapping clinical and immunological findings. Previous therapies for CVI, including intravenous immunoglobulin, have not altered the mortality of the disease. TNF-alpha is a primary cytokine and is elevated in CVI, and specific inhibition of TNF-alpha in this patient was effective in moderating his disease, including his skin disease.
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PMID:Common variable immunodeficiency treated with a recombinant human IgG, tumour necrosis factor-alpha receptor fusion protein. 1126 23

Ventricular remodeling is an extremely complicated process that is not well understood. There seem to be multiple feedback loops that respond to mechanical events as well as to neurohormonal stimulation, cytokine release, and other, yet unidentified, agents. The progression of ventricular remodeling after the index event includes: Myocyte slippage and thinning of infarct area, chamber dilatation. Fibrosis and scar formation. Collagen strut dissolution and excessive accumulation of interstitial matrix. Increased wall stress. Myocyte hypertrophy. Neurohormonal activation. Cytokine release. Ongoing myocyte hypertrophy. Cell apoptosis and necrosis. Continued deterioration of cardiac function. It is impossible to place the sequence of events in order, because the multiple feedback systems create a complex interactive process. A basic awareness of the pathophysiology of ventricular remodeling can aid in understanding current and future treatments for heart failure. It is clear that therapeutic interventions solely aimed at improving cardiac pump function do not slow the progression of heart failure or reduce mortality. Drugs that block the neuroendocrine contribution to the remodeling process have been shown to have a greater impact. Current therapies with angiotensin-converting enzyme inhibition, beta blockade, and aldosterone antagonism are associated with significant reductions in morbidity and mortality in heart failure. Other therapeutic strategies suggested by knowledge of remodeling mechanisms, such as drugs to block cytokines, endothelins, and MMPs, may offer further benefit to patients with heart failure in the future.
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PMID:Ventricular remodeling. 1471 85

The mandatory use of pharmacotherapy in human heart failure (HF) impedes further study of natural history and remodeling mechanisms. We created a sheep model of chronic, severe, ischemic HF [left ventricular (LV) ejection fraction (LVEF) <35% stable over 4 wk] by selective coronary microembolization under general anesthesia and followed hemodynamic, energetic, neurohumoral, structural, and cellular responses over 6 mo. Thirty-eight sheep were induced into HF (58% success), with 23 sheep followed for 6 mo (21 sheep with sufficient data for analysis) after the LVEF stabilized (median of 3 embolizations). Early doubling of LV end-diastolic pressure persisted, as did increases in LV end-diastolic volume, LV wall stress, and LV wall thinning. Contractile impairment (LV end-systolic elastance, LV preload recruitable stroke work, and dobutamine-responsive contractile reserve) and diastolic dysfunction also remained stable. Cardiac mechanical energy efficiency did not recover. Plasma atrial natriuretic peptide levels remained elevated, but rises in plasma aldosterone and renin activity were transient. Collagen content increased 170%, the type I-to-III phenotype ratio doubled in the LV, but right ventricular collagen remained unaltered. Fas ligand cytokine levels correlated with expression of both caspase-3 and -2, suggesting a link in the apoptotic "death cascade." Caspase-3 activity also bore a close relationship to LV meridional wall stress calculated from echocardiographic and intraventricular pressure measurements. We concluded that the stability of chronic untreated severe ischemic HF depends on the recruitment of myocardial remodeling mechanisms that involve an interaction among hemodynamic load, contractile efficiency/energetics, neurohumoral activation, response of the extracellular matrix, wall stress, and the myocyte apoptotic pathway.
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PMID:Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses. 1514 56

Bones conduct sound in the middle ear. The three ossicles-the malleus, incus, and stapes-form a chain that transmits vibrations from the tympanic membrane to the oval window of the inner ear. Little is known about bone remodeling events in these ossicles and about potential effects of osteoporosis on hearing loss. Osteoclastic bone resorption is enhanced in Opg(-/-) mice lacking osteoprotegerin, which is a soluble decoy receptor for the osteoclastogenic cytokine RANKL. We asked whether auditory ossicles are resorbed in Opg(-/-) mice, and whether these mice suffer from impaired auditory function. All three ossicles in Opg(-/-) mice showed thinning, especially at the malleal manubrium and incus body. Most notably, unlike in the case in wild-type mice, the junction between the stapes and the otic capsule was fixed in Opg(-/-) mice, and the stapedial footplate was thinner and broader. Radiological analyses revealed that malleal cortical thickness was positively correlated with tibial bone mineral density in Opg(-/-) and control littermate mice. Furthermore, progressive hearing loss was detected in Opg(-/-) mice starting at 6 to 15 weeks of age. These data suggest that osteoprotegerin plays a crucial role in hearing by protecting the auditory ossicles and otic capsule from osteoclastic bone resorption.
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PMID:Resorption of auditory ossicles and hearing loss in mice lacking osteoprotegerin. 1656 35

Previous studies have shown that 1 wk after permanent coronary artery ligation in rats, some cellular mechanisms involving TNF-alpha occur and contribute to the development of cardiac dysfunction and subsequent heart failure. The aim of the present study was to determine whether similar phenomena also occur after ischemia-reperfusion and whether cytokines other than TNF-alpha can also be involved. Anesthetized male Wistar rats were subjected to 1 h coronary occlusion followed by reperfusion. Cardiac geometry and function were assessed by echocardiography at days 5, 7, 8, and 10 postligation. Before death, heart function was assessed in vivo under basal conditions, as well as after volume overload. Finally, hearts were frozen for histoenzymologic assessment of infarct size and remodeling. The profile of cardiac cytokines was determined by ELISA and ChemiArray on heart tissue extracts. As expected, ischemia-reperfusion induced a progressive remodeling of the heart, characterized by left ventricular free-wall thinning and cavity dilation. Heart function was also decreased in ischemic rats during the first week after surgery. Interestingly, a transient and marked increase in TNF-alpha, IL-1beta, IL-6, cytokine-induced neutrophil chemoattractant (CINC) 2, CINC3, and macrophage inflammatory protein-3alpha was also observed in the myocardium of myocardial ischemia (MI) animals at day 8, whereas the expression of anti-inflammatory interleukins IL-4 and IL-10 remained unchanged. These results suggest that overexpression of proinflammatory cytokines occurring during the first week after ischemia-reperfusion may play a role in the adaptative process in the myocardium and contribute to early dysfunction and remodeling.
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PMID:Delayed expression of cytokines after reperfused myocardial infarction: possible trigger for cardiac dysfunction and ventricular remodeling. 1787 14

In psoriasis, CD28/B7 costimulatory molecules are well characterized. Here, using the severe combined immunodeficient (SCID) mouse-psoriasis xenograft model, we report therapeutic efficacy of a humanized anti-CD28 monoclonal antibody (FR255734; Astellas Pharmaceuticals Inc., Tokyo, Japan). Transplanted psoriasis plaques on the SCID mouse were treated weekly for 4 weeks with intraperitoneal injections of FR255734 at 10, 3, and 1-mg kg(-1) doses. Groups treated with doses of 10 and 3 mg kg(-1) had significant thinning of the epidermis and reduced HLA-DR-positive lymphocytic infiltrates. The length of the rete pegs changed from 415.2+/-59.6 to 231.4+/-40.4 microm (P<0.005) in the 10-mg kg(-1) group, and from 323.4+/-69.6 to 237.5+/-73.6 microm in the 3-mg kg(-1) group (P=0.002). Positive controls treated with CTLA4-Ig and cyclosporine had significant histological improvement, whereas plaques treated with saline and isotype controls (human and mouse IgG2) remained unchanged. In vitro studies have shown that FR255734 effectively blocked T-cell proliferation and proinflammatory cytokine production. These observations warrant studies to evaluate the efficacy of FR255734 in human autoimmune diseases.
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PMID:FR255734, a humanized, Fc-Silent, Anti-CD28 antibody, improves psoriasis in the SCID mouse-psoriasis xenograft model. 1833 36


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