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At least 235 records · Page 13Linked to original sources

PubMed2004

Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis.

BACKGROUND: Expression of matrix metalloproteinases (MMPs) by infiltrating and intrinsic renal cells is increased in inflammatory conditions, and may correlate with disease activity of glomerulonephritis. We analysed renal expression of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil and monocyte infiltration in renal biopsies of patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and monocyte-derived MMP activators cathepsin G, neutrophil elastase and myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6) associated glomerulonephritis, and in normal renal tissue (n = 4). Double labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68, labelling neutrophils and macrophages. RESULTS: MMP-2-, MMP-3-, MMP-9- and TIMP-1-positive cells were detected in ANCA-associated glomerulonephritis in glomeruli with active inflammation (cellular crescents or fibrinoid necrosis), only occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue, no expression was detected, with the exception of weak mesangial staining for MMP-2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1 correlated with glomerular cathepsin G expression, while the number of MMP-9-expressing cells per glomerulus correlated with the percentage of crescentic glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1 expression correlated with renal function at the time of renal biopsy. CONCLUSIONS: Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1 is increased in active ANCA-associated glomerulonephritis and correlates with inflammatory activity.

Adult↗

PubMed2003

Development and evaluation of a thermoreversible ovule formulation of stampidine, a novel nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide.

Stampidine [2',3'-didehydro-2',3'-dideoxythymidine 5'-[p-bromophenyl methoxyalaninyl phosphate], a prodrug of stavudine (STV/d4T) with improved anti-HIV activity, is undergoing development as a novel nonspermicidal microbicide. Here, we report the stability of stampidine as a function of pH, preparation of a novel thermoreversible ovule formulation for mucosal delivery, its dissolution profile in synthetic vaginal fluid, and its mucosal toxicity potential as well as systemic absorption in the rabbit model. Stampidine was most stable under acidic conditions. Stampidine was solubilized in a thermoreversible ovule formulation composed of polyethylene glycol 400, polyethylene glycol fatty acid esters, and polysorbate 80. Does were exposed intravaginally for 14 days to an ovule formulation with and without 0.5%, 1%, or 2% stampidine corresponding to 1 x 107- to 4 x 107-fold higher than its in vitro anti-HIV IC50 value. Vaginal tissues harvested on Day 15 were evaluated for mucosal toxicity and cellular inflammation. Additionally, does were exposed intravaginally to stampidine, and plasma collected at various time points was assayed by analytical HPLC for the prodrug and its bioactive metabolites. Stampidine did not cause mucosal inflammation. The vaginal irritation scores for 0.5-2% stampidine were within the acceptable range for clinical trials. The prodrug and its major metabolites were undetectable in the blood plasma. The marked stability of stampidine at acidic pH, its rapid spreadability, together with its lack of mucosal toxicity or systemic absorption of stampidine via a thermoreversible ovule may provide the foundation for its clinical development as an easy-to-use, safe, and effective broad-spectrum anti-HIV microbicide without contraceptive activity.

Administration, Intravaginal↗

PubMedDate not supplied

Performance of a hydrogel composite pericardial substitute after long-term implant studies.

A novel composite patch has been tested as a pericardial substitute to reduce adhesion formation after cardiac surgery. The patch consists of poly 2-hydroxyethyl methacrylate (pHEMA) hydrogel reinforced with a polyethylene terephthalate (PET) mesh. The hydrogel-PET composite pericardial patches were implanted in canines for 6, 9, and 12 months. Upon termination, adhesion formation and epicardial reaction to the implant were rated. No adhesions formed between the patch and the native pericardium or epicardium. A thin fibrous layer on the epicardium progressively developed where the patch contacted the heart. The coronary anatomy remained visible. Histologically, the response to the implant was fibrous in nature. No significant signs of cellular inflammation were found. The gross appearance of the retrieved patches was nearly identical to that of preimplant patches. Mechanical tests showed no significant changes (alpha = 0.05) in patch strength or stiffness. Hydrogel water content initially increased during implantation. The thickness of the patch did not change significantly (alpha = 0.05) throughout the study. Scanning electron microscopy (SEM) revealed unequal layers of hydrogel on either side of the PET mesh and cracks in the hydrogel surfaces of retrieved patches. Both SEM and light microscopic observation of the patches showed traces of calcification in patches in the 9 and 12 month studies.

Animals↗

PubMed1989

Effects of iopamidol and iohexol in rat lungs following experimental aspiration.

Experimental aspiration of water soluble contrast agents was performed on rats via transoral endotracheal injection. Iopamidol, iohexol and diatrizoate were the contrast agents tested. One group of rats received normal saline as a control. Adjusted lung weights were measured at 2 and 24 hours post aspiration. Radiographs were taken at 2 and 24 hours post aspiration and scored for abnormal pulmonary air space density. Diatrizoate alone demonstrated an increase in adjusted lung weights. Diatrizoate, iopamidol and iohexol showed abnormal pulmonary air space disease on radiographs at 2 hours but not at 24 hours. Histopathologic examination of rat lungs following aspiration of all three contrasts showed pulmonary vascular congestion and perivascular edema. Iopamidol showed evidence of acute cellular inflammation. Iohexol provoked a pulmonary alveolar macrophage response.

Animals↗

PubMed1997

Immunohistochemical localization of nitric oxide synthase and the oxidant peroxynitrite in lung transplant recipients with obliterative bronchiolitis.

BACKGROUND: Obliterative bronchiolitis (OB) is a disease affecting a large percentage of lung and heart-lung transplant recipients. Histologically, the disease is characterized by inflammation, cellular proliferation, and obliteration of terminal airways. METHODS: We investigated the production of inducible and constitutive nitric oxide synthases and peroxynitrite by immunohistochemistry in the lungs of control subjects (n=14) compared with those of transplant recipients with OB (n=8). RESULTS: Strong immunoreactivity for inducible nitric oxide synthase and nitrotyrosine, a marker of protein nitration by peroxynitrite, was seen in inflammatory cells, airway epithelium, and vascular endothelium of patients with OB, compared with little immunoreactivity in control lungs. Immunoreactivity for constitutive nitric oxide synthase was abundant in the airway epithelium and vascular endothelium of control lungs, however, it was decreased in airway epithelial cells and arterial endothelial cells of patients with OB. CONCLUSIONS: We conclude that increased formation of the potent oxidant peroxynitrite and decreased production of endothelial nitric oxide may contribute to the functional and morphological abnormalities of OB.

Bronchiolitis Obliterans↗

PubMed2000

Protection of autotransplanted pig kidneys from ischemia-reperfusion injury by polyethylene glycol.

BACKGROUND: Ischemia-reperfusion injury (IRI) is often responsible for graft rejection and leads to delayed graft function of cadaveric kidneys. We have shown that adding polyethylene glycol (PEG 20M) to the preservation solutions helps protect isolated perfused pig kidneys against cold ischemia and reperfusion injury. METHODS: We compared the effects of adding PEG to a simplified high-K+ perfusion solution of cold-stored kidneys to Euro-Collins or University of Wisconsin solutions on the function of reperfused autotransplanted pig kidneys. The left kidney was cold-flushed with the preservation solutions and stored for 48 hr at 4 degrees C before reimplantation. Creatinine clearance and fractional excretion of sodium were analyzed 2 days before surgery and over 7 days after transplantation. Histological sections were obtained 40 min after reperfusion and on day 7 after surgery. RESULTS: Adding PEG to the perfusate significantly reduced IRI from autotransplanted pig kidneys. Creatinine clearance was significantly higher and fractional excretion of sodium was significantly lower in pigs transplanted with kidneys cold-flushed with PEG-supplemented perfusate than in those flushed with Euro-Collins or University of Wisconsin solutions. PEG supplementation also better preserved the integrity of kidney cells and markedly reduced interstitial cell infiltrates. CONCLUSION: PEG protects against IRI and reduces early cellular inflammation. PEG may impair the recruitment and migration of leukocytes into retransplanted pig kidneys. Cold preservation of donor organs with PEG-supplemented solutions may therefore help limit IRI in human renal transplantation.

Animals↗

PubMed1999

The pathogenesis of pterygia.

Pterygium is an active, invasive, inflammatory process, a key feature of which is focal limbal failure. In a two-stage process, "conjunctivalization" of the cornea occurs with tissue characterized by extensive chronic-inflammation, cellular proliferation, connective tissue remodeling, and angiogenesis. An understanding of this process has resulted in efforts aimed at limbal reconstruction, which is considered the gold standard for surgical care. Although good results have been obtained with other treatment methods, a long-term approach to follow-up with at least 5-year survival figures is desirable. Sophisticated analyses of the tear film and surface epithelium in patients with pterygium may help explain symptoms. The efficacy, at least in the short term, of nonsteroidal anti-inflammatory drugs in the treatment of inflamed pterygia has been confirmed. Corneal topographic analysis has shown that surgery reduces induced astigmatism and also causes subtle changes that may explain postsurgical improvements in vision.

Conjunctiva↗

PubMed2003

Lipopolysaccharide concentration and bone resorption in cholesteatoma.

HYPOTHESIS: There is a relationship between the local lipopolysaccharide (LPS) concentration in cholesteatoma and local bone resorption in chronic otitis media (COM) with cholesteatoma. BACKGROUND: During the past decade, it has become known that the recruitment of osteoclasts is the main causative factor that induces bone destruction in COM with cholesteatoma. Cellular inflammation factors like cytokines may trigger the osteoclast. Sequel to this, LPS is able to up-regulate cytokines. This makes it of interest to study whether the local LPS concentration is related to bone resorption in cholesteatoma. MATERIALS AND METHODS: Twenty-four cholesteatoma samples and control tissue from COM patients without cholesteatoma were collected. During surgery, the degree of bone resorption was established and classified. Retrospectively, the authors checked whether patients had chronic purulent otorrhea. LPS concentration of the tissue samples was measured by the limulus amebocyte lysate test. The one-way analysis of variance test was used to determine the relation between LPS concentration, otorrhea, and local bone resorption. RESULTS: A significantly higher concentration of LPS was measured in samples from patients with cholesteatoma with bone resorption and otorrhea compared with cholesteatoma without bone resorption and control tissue. There were no significant differences between the LPS levels of the different groups of patients with bone resorption. CONCLUSION: It is suggested that LPS is one of the first factors in the cascade of bone resorption in COM with cholesteatoma.

Bone Resorption↗

PubMed2006

The use of chemical cross-linking and mass spectrometry to elucidate the tertiary conformation of lipid-bound apolipoprotein A-I.

PURPOSE OF REVIEW: The purpose of this review is to highlight recent advances in mass spectrometry and its use for identifying the lipid-bound conformation of apolipoprotein A-I. Given the current interest in understanding the structure of HDL apolipoprotein A-I, this approach seems ideal in assessing its dual role as mediator of lipid efflux and modulator of cellular inflammation. RECENT FINDINGS: A large number of different technical approaches have been employed over the past 25 years in attempts to solve the lipid-bound conformation of apolipoprotein A-I. Since the X-ray crystal structure of lipid-free Delta43 apolipoprotein A-I was reported in 1997, a 'double belt' model describing lipid-bound apolipoprotein A-I conformation for recombinant HDL has prevailed. Recent studies have focused on determining the exact helix-helix registry and salt-bridging partners found on a two apolipoprotein A-I molecule disc as well as on spherical HDL particles. Investigations are all aimed at defining the conformation of lipid-bound apolipoprotein A-I which may provide an explanation for how specific domains of apolipoprotein A-I interact with important HDL-modifying proteins that ultimately determine the apolipoprotein's fate in circulation. SUMMARY: Recent advances in mass spectrometric sequencing of cross-linked peptides provide an excellent tool to help define protein tertiary structure. This approach has provided refined structural information on apolipoprotein A-I folding which had eluded all previous approaches.

Apolipoprotein A-I↗

PubMed2006

Chronic allograft nephropathy: current concepts and future directions.

The paradigm that chronic rejection causes all progressive late allograft failure has been replaced by a hypothesis of cumulative damage, where a series of time-dependent immune and nonimmune mechanisms injure the kidney and lead to chronic interstitial fibrosis and tubular atrophy, representing a final common pathway of injury and its consequent fibrotic healing response. Allograft damage is common, progressive, time-dependent, clinically important and modified by immunosuppression. Early after transplantation, tubulointerstitial damage is predominantly related to ischemia reperfusion injury, acute tubular necrosis, acute and subclinical rejection and/or calcineurin inhibitor nephrotoxicity, superimposed on preexisting donor disease. Later, cellular inflammation lessens and is replaced by microvascular and glomerular injury from calcineurin inhibitor nephrotoxicity, hypertension, immune-mediated fibrointimal vascular hyperplasia, transplant glomerulopathy and capillary injury, polyoma virus and/or recurrent glomerulonephritis. Additional mechanisms of injury include internal architectural disruption of the kidney, cortical ischemia, persistent chronic inflammation, replicative senescence, cytokine excess and fibrosis induced by epithelial-to-mesenchymal transition. Current understanding of the etiology, pathophysiology and evolution of pathological changes are detailed. An approach to histological assessment of the individual failing graft are presented and a series of postulates are defined for future studies of chronic allograft nephropathy.

Forecasting↗

PubMed2004

S100 proteins in the epidermis.

The S100 proteins comprise a family of 21 low molecular weight (9-13 kDa) proteins that are characterized by the presence of two calcium-binding EF-hand motifs. Fourteen S100 protein genes are located within the epidermal differentiation complex on human chromosome 1q21 and 13 S100 proteins (S100A2, S100A3, S100A4, S100A6, S100A7, S100A8, S100A9, S100A10, S100A11, S100A12, S100A15, S100B, and S100P) are expressed in normal and/or diseased epidermis. S100 proteins exist in cells as anti-parallel hetero- and homodimers and upon calcium binding interact with target proteins to regulate cell function. S100 proteins are of interest as mediators of calcium-associated signal transduction and undergo changes in subcellular distribution in response to extracellular stimuli. They also function as chemotactic agents and may play a role in the pathogenesis of epidermal disease, as selected S100 proteins are markedly overexpressed in psoriasis, wound healing, skin cancer, inflammation, cellular stress, and other epidermal states.

Epidermis↗

PubMed1986

The distribution of immunoglobulins and albumin in the central nervous system in acute experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) was induced in young male Lewis rats. Immunohistochemical visualisation of albumin and IgG in the nervous tissue was performed at intervals after induction. The results were correlated to the histological appearance of the tissue. Albumin appeared in the tissue about day 10, 1-2 days before IgG. Within one day both proteins spread from sharply defined perivascular subpial locations to diffuse distribution throughout the tissue. Cellular inflammation was not seen until 3-4 days after extravasation of proteins. The cells also spread from perivascular locations to a diffuse infiltration of the tissue.

Acute Disease↗

PubMed1993

Tick salivary gland extract and interleukin-2 stimulation enhance susceptibility of lymphocytes to infection by Theileria parva sporozoites.

Intracellular parasites show host cell specificity, and precise information on the range of host cells is a prerequisite for the identification of host molecules that account for the specificity and are involved in entry processes. The sporozoite stage of the tick-borne protozoan parasite Theileria parva binds to and enters bovine lymphocytes, but precise information on the susceptibility of other cell types present at the tick attachment site is unavailable. We quantitatively examined the susceptibility of cell types known to be present at the tick attachment site by a previously established in vitro assay. Apart from lymphocytes, sporozoites also bind to and enter macrophages and afferent lymph veiled cells; they do not bind to or enter fibroblasts, granulocytes, or erythrocytes. Sporozoites are not phagocytosed by the macrophages or veiled cells but enter them as they do lymphocytes. Since the tick attachment site is a region of cellular inflammation, we also examined the effects of agents known to be present in this area on lymphocyte susceptibility. Short-term preincubation of lymphocytes with tick salivary gland extract, with compounds that induce lymphocyte proliferation, or with interleukin-2 (IL-2), a cytokine produced by activated lymphocytes, increased host cell susceptibility by between 30 and 60%. The IL-2-induced increase in host cell susceptibility could be prevented by treating the lymphocytes with the monoclonal antibody IL-A 111, which reacts with the bovine IL-2 receptor alpha chain and inhibits IL-2-driven cell proliferation. The changes induced by tick salivary gland extract and IL-2 occurred in less than 90 min. Similarly, peripheral blood mononuclear cells from an animal previously immunized with a nonrelated antigen (trypanosome variant surface glycoprotein) and stimulated in vitro with the same antigen showed increases in host cell susceptibility of between 70 and 125%. In contrast, treatment of lymphocytes with gamma interferon did not induce any increase in host cell susceptibility.

Animals↗

PubMed2006

Spatiotemporal analysis of purkinje cell degeneration relative to parasagittal expression domains in a model of neonatal viral infection.

Infection of newborn Lewis rats with Borna disease virus (neonatal Borna disease [NBD]) results in cerebellar damage without the cellular inflammation associated with infections in later life. Purkinje cell (PC) damage has been reported for several models of early-life viral infection, including NBD; however, the time course and distribution of PC pathology have not been investigated rigorously. This study examined the spatiotemporal relationship between PC death and zonal organization in NBD cerebella. Real-time PCR at postnatal day 28 (PND28) revealed decreased cerebellar levels of mRNAs encoding the glycolytic enzymes aldolase C (AldoC, also known as zebrin II) and phosphofructokinase C and the excitatory amino acid transporter 4 (EAAT4). Zebrin II and EAAT4 immunofluorescence analysis in PND21, PND28, PND42, and PND84 NBD rat cerebella revealed a complex pattern of PC degeneration. Early cell loss (PND28) was characterized by preferential apoptotic loss of zebrin II/EAAT4-negative PC subsets in the anterior vermis. Consistent with early preferential loss of zebrin II/EAAT4-negative PCs in the vermis, the densities of microglia and the Bergmann glial expression of metallothionein I/II and the hyaluronan receptor CD44 were higher in zebrin II/EAAT4-negative zones. In contrast, early loss in lateral cerebellar lobules did not reflect a similar discrimination between PC phenotypes. Patterns of vermal PC loss became more heterogeneous at PND42, with the loss of both zebrin II/EAAT4-negative and zebrin II/EAAT4-positive neurons. At PND84, zebrin II/EAAT4 patterning was abolished in the anterior cerebellum, with preferential PC survival in lobule X. Our investigation reveals regional discrimination between patterns of PC subset loss, defined by zebrin II/EAAT4 expression domains, following neonatal viral infection. These findings suggest a differential vulnerability of PC subsets during the early stages of virus-induced neurodegeneration.

Animals↗

PubMed2004

Functional antagonism of chemokine receptor CCR1 reduces mortality in acute pneumovirus infection in vivo.

We present an antiviral-immunomodulatory therapeutic strategy involving the chemokine receptor antagonist Met-RANTES, which yields significant survival in the setting of an otherwise fatal respiratory virus infection. In previous work, we demonstrated that infection with the natural rodent pathogen pneumonia virus of mice involves robust virus replication accompanied by cellular inflammation modulated by the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha). We found that the antiviral agent ribavirin limited virus replication in vivo but had no impact on morbidity and mortality associated with this disease in the absence of immunomodulatory control. We show here that ribavirin reduces mortality, from 100% to 10 and 30%, respectively, in gene-deleted CCR1(-/-) mice and in wild-type mice treated with the small-molecule chemokine receptor antagonist, Met-RANTES. As MIP-1alpha-mediated inflammation is a common response to several distantly related respiratory virus pathogens, specific antiviral therapy in conjunction with blockade of the MIP-1alpha/CCR1 inflammatory cascade may ultimately prove to be a useful, generalized approach to severe respiratory virus infection and its pathological sequelae in human subjects.

Acute Disease↗

PubMed1985

Cellular immunohistopathology of acute, subacute, and chronic synovitis in rheumatoid arthritis.

Cellular inflammation in rheumatoid arthritis (RA) synovial membrane was studied in biopsy specimens taken at different stages of synovitis and disease. Patients were classified into three subgroups: acute RA, subacute RA, and chronic RA. Inflammatory cells were characterised by a histochemical esterase method and immunohistochemical peroxidase-antiperoxidase (PAP) and avidin-biotin-peroxidase (ABC) staining. The amounts and distribution of inflammatory cells were different in various stages of the synovitis. In acute onset RA monocytes and granulocytes predominated, suggesting that the beginning of rheumatoid inflammation is similar to inflammatory reaction in general. The presence of T cells and also of plasma cells in subacute RA suggests underlying subclinical changes also in apparently healthy joints in RA. The most typical feature of prolonged synovitis in chronic RA was its intensity, characterised by the presence of large T cell and plasma cell infiltrates. Our findings suggest that the immunological mechanisms are secondary to the tissue damage caused by the initial inflammatory events of unknown cause. However, the immunological mechanisms may still play a central role in the aetiopathogenesis, because findings in chronic RA suggest a defective down-regulation of the immune response.

Acute Disease↗

PubMed1986

CNS toxoplasmosis in acquired immune deficiency syndrome: a clinical-pathological-radiological review of 12 cases.

From January 1981 to January 1983 acquired immune deficiency syndrome (AIDS) was diagnosed in 90 patients admitted to Kings County Hospital-Downstate Medical Center. CNS involvement occurred in 18 patients of whom 12 had toxoplasmosis confirmed by biopsy or necropsy. Pathological specimens from these 12 patients were notable for a marked diminution or absence of cellular inflammation. Each patient had elevated serological studies for toxoplasma. AIDS presented with symptoms referable to CNS toxoplasma in eight patients. In the remaining four patients, toxoplasma was found late in the course of the illness. CT showed either ring enhancing lesions or solid nodules. The course was uniformly fatal, though patients treated continuously with pyrimethamine and sulfadiazine survived longer.

Acquired Immunodeficiency Syndrome↗

PubMed2003

TGF-beta1 causes airway fibrosis and increased collagen I and III mRNA in mice.

BACKGROUND: Subepithelial collagen and extracellular matrix protein deposition are important pathophysiological components of airway remodelling in chronic asthma. Animal models based on the local reaction to antigens show structural alterations in the airway submucosal region and provide important information regarding disease pathophysiology. We describe a murine model of peribronchial fibrosis using intratracheally instilled transforming growth factor (TGF)-beta(1) in BALB/C mice that facilitates a mechanistic approach to understanding the cellular and molecular pathways leading to airway fibrosis. METHODS: BALB/C mice were intratracheally instilled with either TGF-beta(1) or buffered saline. Airway fibrosis was assessed by light microscopy, hydroxyproline content, and polymerase chain reaction (PCR) for collagen I and III on microdissected airway samples. The lysyl oxidase inhibitor beta-aminoproprionitrile (BAPN) was administered to TGF-beta(1) treated mice to block airway collagen deposition. Airway hyperresponsiveness was also measured after treatment with TGF-beta(1). RESULTS: During the 7 days after administration of TGF-beta(1) the mice developed increased subepithelial collagen which could be blocked by BAPN. Increased mRNAs for collagen types I and III were seen in microdissected airways 1 week after TGF-beta(1), and significantly increased total collagen was found in the airways 4 weeks after TGF-beta(1). A detectable increase in airway hyperreactivity occurred. CONCLUSIONS: This new model should facilitate detailed study of airway remodelling that occurs in the absence of detectable cellular inflammation, and allow examination of the functional consequences of a major structural alteration in the conducting airways uncomplicated by inflammatory cell influx.

Aminopropionitrile↗