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PubMed2000

The effects of local administration of lactoferrin on inflammation in murine autoimmune and infectious arthritis.

OBJECTIVE: To determine whether lactoferrin can modify articular inflammation in murine models of autoimmune and septic arthritis. METHODS: Collagen arthritis was induced in DBA/1 mice and Staphylococcus aureus septic arthritis in Swiss mice. Joints with established inflammation were injected periarticularly with 0.5 mg or 1 mg of human lactoferrin, and arthritis was monitored for 3 days. RESULTS: DBA/1 mice injected with lactoferrin showed significantly suppressed local inflammation for up to 3 days, achieving up to 71% of the effect of corticosteroid. Periarticular injection of 125I-lactoferrin confirmed that 25% of lactoferrin was retained in paws after 6 hours. Serum levels of interleukin-6, however, were not significantly reduced, suggesting a predominantly local antiinflammatory effect. Similarly, local, periarticular administration of lactoferrin into S aureus-infected Swiss mice significantly suppressed paw inflammation and did not enhance bacterial survival. CONCLUSION: Lactoferrin may have clinical utility in reducing articular inflammation, particularly in septic arthritis, in which antiinflammatory effects may be achieved without promoting bacterial survival.

Administration, Topical↗
PubMed1989

Requirements for flare reactions of joint inflammation induced in mice by cloned MT4+, Lyt-2- T cells.

Joint inflammation was induced in C57B1/6 mice by injection of cloned MT4+, Lyt-2- T cells specific for the antigen methylated bovine serum albumin (mBSA), together with mBSA. In this model, after waning of the inflammation, flare reactions can be induced by a rechallenge with the specific antigen. Herein we show that such flare reactions can still be induced several weeks after waning of the joint inflammation, as was demonstrated both in normal C57B1/6 mice and in athymic C57B1 nude mice. The results in the latter group indicate that T cells of the recipient mice are not necessary for the elicitation of flare reactions. On histologic examination, the inflammatory infiltrates in the knee joints of the nude mice appeared to be mainly granulocytic. The cloned T cells persisted and remained functionally reactive in the knee joint for at least 2 weeks in the absence of the antigen, and thus, in the absence of inflammation. In view of the similarities between induced joint inflammation in mice and rheumatoid arthritis in humans, these data may be relevant to our understanding of the processes involved in the latter disease.

Animals↗
PubMed2003

Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis.

OBJECTIVE: To study the role of the activating Fc gamma receptor types I and III (Fc gamma RI and Fc gamma RIII, respectively) and the inhibiting Fc gamma receptor II (Fc gamma RII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune complexes. METHODS: Immune complex-mediated arthritis (ICA) was passively induced by lysozyme-antilysozyme complexes in Fc gamma RI-, Fc gamma RIII-, and Fc gamma RII-knockout mice and their wild-type controls. Total knee joints were isolated to study inflammation and cartilage destruction (loss of proteoglycans [PGs], chondrocyte death, matrix metalloproteinase [MMP]-mediated neoepitope [VDIPEN] expression, and erosion). The presence of an active phenotype of macrophages was studied by detection of myeloid-related proteins 8 and 14 (MRP8 and MRP14, respectively). RESULTS: Influx and activation of inflammatory cells (MRP expression) during ICA was decreased in Fc gamma RIII-deficient mice and enhanced in mice lacking Fc gamma RII. Mild cartilage destruction reflected by loss of PGs was consistent with the degree of inflammation. Mice lacking Fc gamma RIII showed almost no PG depletion, whereas in Fc gamma RII(-/-) mice, PG depletion was increased 3-7-fold in various cartilage areas. Initiation of erosive cartilage destruction, as reflected by MMP-mediated VDIPEN expression, was reduced in Fc gamma RIII(-/-) and Fc gamma RI(-/-) mice, directing the two different critical steps of cellular influx and subsequent activation. These aspects were enhanced in Fc gamma RII(-/-) mice. In Fc gamma RI(-/-) and Fc gamma RIII(-/-) mice, VDIPEN expression was 90-99% lower, whereas in Fc gamma RII(-/-) mice, VDIPEN expression was increased 4-fold. Chondrocyte death was reduced in Fc gamma RIII(-/-) mice (68% lower) and enhanced in Fc gamma RII(-/-) mice (6-12-fold higher). Progression of arthritis and erosion of the cartilage surface were markedly elevated in Fc gamma RII(-/-) arthritic joints. CONCLUSION: During ICA, Fc gamma RIII is the dominant activating receptor mediating joint inflammation, whereas both Fc gamma RI and Fc gamma RIII are involved in cartilage destruction. Fc gamma RII inhibits both joint inflammation and severe cartilage destruction during ICA.

Animals↗
PubMed2003

Role of the tissue factor pathway in synovial inflammation.

OBJECTIVE: Clinical and experimental evidence suggests that extravascular fibrin deposition in arthritic joints is prominent and deleterious. The aim of this study was to investigate the contributions of tissue factor (TF) and its inhibitor, TF pathway inhibitor (TFPI), in arthritis. METHODS: Synovial tissue specimens obtained from 10 patients with rheumatoid arthritis (RA) and 12 patients with osteoarthritis (OA) were scored histologically for inflammation and fibrin content. TF and TFPI levels were assayed at antigenic and functional levels. TF messenger RNA (mRNA) levels were determined using RNase protection assays. The effect of TF inhibition in murine antigen-induced arthritis (AIA) was assessed by administering systemically active site-blocked activated factor VIIa (FVIIai). RESULTS: Functional TF activity was significantly increased in synovial membranes from RA patients compared with those from OA patients. In contrast, no difference in TF mRNA and TF antigenic levels was observed between these 2 groups. This discrepancy can be accounted for by TFPI, because we observed a negative correlation between TF activity and TFPI activity. There was a significant difference between the RA and OA groups in terms of synovial inflammation, with more inflammation observed in the RA group. Most importantly, TF activity was associated with fibrin (P = 0.024) and with histologic inflammation (P = 0.03) scores. In AIA, inhibition of TF-induced coagulation by FVIIai led, on day 9 of arthritis, to decreased synovial thickness and decreased articular cartilage damage, although only the latter difference between controls and treated mice reached significance (P < 0.04). Finally, in FVIIai-treated mice, there was a strong negative association between the prothrombin time and intraarticular fibrin deposition. CONCLUSION: Our results show that TF expression in arthritic synovial tissue favors extravascular coagulation and may play a role in inflammation in RA. In this context, TF inhibitors may be of therapeutic value.

Aged↗
PubMed2003

Inhibition of monosodium urate monohydrate crystal-induced acute inflammation by retrovirally transfected prostaglandin D synthase.

OBJECTIVE: Hematopoietic prostaglandin D synthase (H-PGDS) is a key enzyme in the production of prostaglandin D and its J series metabolites. We evaluated the antiinflammatory effect of retrovirally transfected H-PGDS in order to investigate the role of H-PGDS in monosodium urate monohydrate (MSU) crystal-induced acute inflammation. METHODS: Expression of endogenous PGDS in a murine air-pouch model of MSU crystal-induced acute inflammation was determined by real-time polymerase chain reaction. H-PGDS complementary DNA (cDNA) was retrovirally transfected into C57BL/6J fibroblasts, and the cells were designated as C57-PGDS cells. Production of prostaglandins by C57-PGDS cells was measured by enzyme immunoassay. The effect of C57-PGDS cells on crystal-induced inflammation was investigated. RESULTS: Injection of the crystals caused a rapid decrease in H-PGDS expression by infiltrating cells and by the soft tissues around the air pouches. In contrast, expression of interleukin-1beta (IL-1beta) and macrophage inflammatory protein 2 (MIP-2) as well as cellular infiltration were significantly increased during the early stage of inflammation. C57-PGDS cells, but not control cells, produced an increased amount of PGD(2) in vitro, but suppressed production of PGE(2). Injection of C57-PGDS cells into air pouches inhibited cellular infiltration and MIP-2 and IL-1beta expression. CONCLUSION: In this murine air-pouch model of MSU crystal-induced inflammation, retrovirally transfected H-PGDS cDNA could reduce cellular infiltration, at least partly by inhibiting MIP-2 and IL-1beta. These findings suggest that gene therapy with H-PGDS may be useful for treating inflammatory diseases.

Acute Disease↗
PubMed2004

Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction.

OBJECTIVE: To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (IL-1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF-driven arthritis model. METHODS: Human TNF-transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically. RESULTS: Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL-1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra. CONCLUSION: Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.

Animals↗
PubMed1996

Inhibition and prevention of monosodium urate monohydrate crystal-induced acute inflammation in vivo by transforming growth factor beta1.

OBJECTIVE: We investigated the effects of transforming growth factor beta 1 (TGF beta 1) on monosodium urate monohydrate (MSU) crystal-induced acute inflammation in vivo. METHODS: One hour after MSU crystal-induced acute inflammation was produced in the rat subcutaneous air pouch model, the effects of recombinant human TGF beta 1 (rHuTGF beta 1; 10-100 pg/animal) and ultrapure TGF beta 1 (UPTGF beta 1; 100 and 500 pg/animal) were assessed, based on absolute and differential white blood cell counts in the exudate. The effects of 10 pg of rHuTGF beta 1 preincubated with a specific anti-TGF beta antibody, and the effects of coinjection of crystals and rHuTGF beta 1, were also studied. RESULTS: UPTGF beta 1 and rHuTGF beta 1 markedly reduced MSU crystal-induced inflammation. Recombinant human TGF beta 1 also reduced inflammation when administered concomitantly with MSU crystals. Moreover, rHuTGF beta 1 and UPTGF beta 1, injected 1 hour after MSU crystal injection, reduced the inflammatory response in a dose-dependent manner. Injection of rHuTGF beta 1 (100 pg/animal) resulted in a > 90% reduction in the maximal white blood cell count, achieved 6 hours after crystal injection. Preincubation of rHuTGF beta 1 with a specific anti-TGF beta 1 antibody significantly (P < 0.01) reversed the inhibitory effect of rHuTGF beta 1 on the inflammatory response. Consistent with the regulation of inflammatory cell recruitment into the joint, the percentage of monocytes markedly decreased (P < 0.01) following local injection with rHuTGF beta 1 6 hours after MSU crystal injection. CONCLUSION: Exogenous TGF beta 1 prevents and inhibits MSU crystal-induced acute inflammation in vivo. Its role in the self-limitation of gouty attacks deserves consideration, among the various other factors involved.

Acute Disease↗
PubMed2006

Transglutaminase 2 limits murine peritoneal acute gout-like inflammation by regulating macrophage clearance of apoptotic neutrophils.

OBJECTIVE: Monosodium urate monohydrate (MSU) crystals have remarkable inflammatory potential. However, gouty inflammation is spontaneously self-limited, an occurrence recognized since antiquity. Gouty synovitis is driven and sustained by neutrophil influx. Importantly, macrophage phagocytosis of apoptotic (but not necrotic) neutrophils is antiinflammatory. Therefore, we tested the hypothesis that efficient clearance of apoptotic neutrophils by macrophages is one of the factors that restrains the progression of gouty inflammation. Macrophage expression of transglutaminase 2 (TG2), a multifunctional protein with reciprocally regulated transamidation and purine nucleotide-binding activities, promotes apoptotic leukocyte uptake. In this study, we tested the specific role of macrophage TG2 expression in MSU crystal-induced inflammation. METHODS: We studied MSU crystal-induced peritonitis in TG2-/- and congenic TG2+/+ mice. We also studied the effects of TG2 on apoptotic cell uptake by cultured macrophages. RESULTS: TG2-/- mice demonstrated more progressive neutrophilic accumulation than did TG2+/+ mice, which was associated with delayed clearance of apoptotic neutrophils during MSU crystal-induced peritonitis. We observed defective phagocytosis of apoptotic leukocytes by TG2-/- peritoneal macrophages, which was corrected by soluble extracellular TG2. Transamidation catalytic activity of TG2 was not required to mediate macrophage uptake of apoptotic leukocytes. In contrast, the TG2 nucleotide binding site residue K173 was critical for this TG2 function. TG2 bound to GDP, ADP, or ATP (but not to GTP) rescued defective apoptotic leukocyte uptake by TG2-/- macrophages. CONCLUSION: Enhancement of apoptotic neutrophil uptake by macrophage-derived TG2 restrains gout-like neutrophilic peritoneal inflammation. Differential binding of TG2 by purine nucleotides may contribute to clinical variability in the extent and duration of gouty inflammation.

Animals↗
PubMed2007

Association between reduced levels of MEFV messenger RNA in peripheral blood leukocytes and acute inflammation.

OBJECTIVE: Familial Mediterranean fever (FMF) is associated with more than 70 missense mutations in the MEFV gene. The purpose of this study was to investigate the relative expression of messenger RNA (mRNA) for the MEFV gene in peripheral blood leukocytes (PBLs) obtained from patients with FMF during attacks of acute abdominal inflammation as well as during asymptomatic periods. METHODS: We studied 16 patients with FMF during an attack of acute peritonitis and 17 otherwise healthy individuals who were undergoing surgery because of acute appendicitis. Blood samples were collected from both groups of patients during both acute inflammatory and asymptomatic periods. Relative levels of MEFV mRNA in PBLs were detected with real-time reverse transcriptase-polymerase chain reaction using LightCycler, with 2 sets of primers for the MEFV gene (exons 7-10 and exons 2-3) and with primers for CIAS1 and PSTPIP1 genes. Expression levels were compared with beta(2)-microglobulin as an internal control. RESULTS: MEFV expression was reduced in FMF patients during asymptomatic periods as compared with the non-FMF controls (P < 0.001). We observed a further decrease in MEFV expression in FMF patients during periods of inflammation (P = 0.01). Reduced levels of MEFV mRNA were also noted during the preoperative period as compared with asymptomatic periods in control patients with acute appendicitis (P = 0.01). CIAS1 expression in PBLs from patients with FMF was also found to be lower than that in the control patients. However, CIAS1 expression did not change with acute inflammation. CONCLUSION: This study confirmed that reduced expression of the MEFV gene is associated with inflammation and that it may be one of the pathogenic mechanisms of the attacks of inflammation in FMF patients, along with disease-associated variations in pyrin.

Acute Disease↗
PubMed2003

Vanadium-induced apoptosis and pulmonary inflammation in mice: Role of reactive oxygen species.

Pulmonary exposure to metals and metal-containing compounds is associated with pulmonary inflammation, cell death, and tissue injury. The present study uses a mouse model to investigate vanadium-induced apoptosis and lung inflammation, and the role of reactive oxygen species (ROS) in this process. Aspiration of the pentavalent form of vanadium, V (V), caused a rapid influx of polymorphonuclear leukocytes into the pulmonary airspace with a peak inflammatory response at 6 h post-exposure and resolution by 72 h. During this period, the number of apoptotic lung cells which were predominantly neutrophils increased considerably with a peak response at 24 h accompanied by no or minimum necrosis. After 24 h when the V (V)-induced inflammation was in the resolution phase, an increased influx of macrophages and engulfment of apoptotic bodies by these phagocytes was observed, supporting the role of macrophages in apoptotic cell clearance and resolution of V (V)-induced lung inflammation. Electron spin resonance (ESR) studies using lavaged alveolar macrophages showed the formation of ROS, including O(2)(*-), H(2)O(2), and (*)OH radicals which were confirmed by inhibition with free radical scavengers. The mechanism of ROS generation induced by V (V) involved the activation of an NADPH oxidase complex and the mitochondrial electron transport chain. The ROS scavenger, catalase (H(2)O(2) scavenger), effectively inhibited both lung cell apoptosis and the inflammatory response, whereas superoxide dismutase (SOD) (O(2)(*-) scavenger) and the metal chelator, deferoxamine (inhibitor of (*)OH generation by Fenton-like reactions) had lesser effects. These results indicate that multiple oxidative species are involved in V (V)-induced lung inflammation and apoptosis, and that H(2)O(2) plays a major role in this process.

Administration, Inhalation↗
PubMed1999

Intestinal inflammation in adhesion molecule-deficient mice: an assessment of P-selectin alone and in combination with ICAM-1 or E-selectin.

Biopsy specimens from patients with inflammatory bowel disease have demonstrated an up-regulation of P-selectin, suggesting a role for P-selectin in intestinal inflammation. We examined the role of P-selectin in experimental intestinal inflammation using mice deficient in P-selectin alone or in combination with either ICAM-1 or E-selectin. Colitis was induced using acetic acid or trinitrobenzene sulfonic acid (TNBS). Damage scores and neutrophil infiltration 24 h post acetic acid were not different between wild-type and P-selectin- or P-selectin/ICAM-1-deficient mice, whereas P/E-selectin-deficient mice had enhanced leukocyte recruitment and damage. At 72 h an attenuation in damage scores and a slight decrease in neutrophil infiltration was observed in the P- and P/ICAM-deficient animals. The P/E-selectin-deficient mice maintained enhanced leukocyte recruitment and damage. In wild-type mice P-selectin expression was elevated 48 and 72 h post acetic acid-induced inflammation. Surprisingly, P-selectin or P-selectin/ICAM-1 deficiency did not improve the inflammation induced by TNBS over 7 days. In fact, increased mortality was observed. Anti-adhesion therapy may play only a limited, beneficial role and often a detrimental role in intestinal inflammation.

Acetates↗
PubMed1992

Therapeutic effect of Ga-Al-As diode laser irradiation on experimentally induced inflammation in rats.

We produced experimental inflammation models in rats by carrageenin and studied the effect of Ga-Al-As diode laser irradiation (780 nm, continuous wave, 31.8 j/sec/cm2, spot size of 0.2 mm) on inflamed regions compared with those of indomethacin, a potent anti-inflammatory agent. We found that a low-power infrared laser has an anti-inflammatory effect on carrageenin inflammation. A low-power laser inhibits: (1) the increase of vascular permeability during the occurrence of an acute inflammation in the carrageenin-air-pouch model, (2) edema in the acute stage in the carrageenin-paw-edema model, and (3) the granuloma formation in the carrageenin-granuloma model after receiving laser irradiation once daily. In all cases, irradiation for less than 10 min was sufficient to inhibit the inflammation by 20-30%. The inhibitory effect of laser irradiation was not comparable to that of indomethacin (4 mg/kg, i.o.) in the air-pouch model and the paw-edema model, whereas laser irradiation was more potent than that of daily administration of indomethacin (1 mg/kg, i.o.) in the granuloma model. In future studies of the mechanism of laser effect, it should be noted that irradiating a rat twice, before and after the provocation of inflammation, was essential in order to achieve an effective inhibition of paw-edema.

Aluminum↗
PubMed2002

Fractalkine expression in human renal inflammation.

Immune and inflammatory human renal disease is associated with heavy mononuclear cell infiltration. The trafficking of these cells to extravascular sites is directed by local production of chemokines. Fractalkine is the first described cell-surface anchored chemokine and has potent mononuclear cell-directed adhesion and chemotactic properties. The purpose of this study was to analyse the expression and distribution of fractalkine in human renal inflammation. In situ hybridization and immunohistochemistry were used to study renal biopsies from 15 patients with predominant glomerular inflammation (vasculitic glomerulonephritis) and 15 with predominant tubular and interstitial inflammation (acute renal allograft rejection). Controls comprised non-inflammatory glomerulonephritis and normal tissue. Fractalkine mRNA was predominantly expressed in the major compartment, glomerular or tubulointerstitial, affected by disease and with the strongest expression localized to vascular sites local to inflammation. In acute renal allograft rejection, there was increased expression of fractalkine mRNA by tubular epithelial cells. There was no expression of fractalkine by infiltrating leukocytes and there was only sparse expression in control tissue. Fractalkine mRNA expression correlated with infiltrating leukocyte subsets. Immunohistochemistry confirmed this pattern of expression, with serial section co-localization showing fractalkine expression in areas with macrophage (CD68+) and T cell (CD3+) infiltrates. These expression patterns show that fractalkine is a strong candidate for directing mononuclear cell infiltration in human renal inflammation.

Acute Disease↗
PubMed1994

Role of beta 2 integrins in the recruitment of phagocytic cells in joint inflammation in the rat.

Adhesion molecules of the beta 2 family of integrins play an important role in adhesion and migration of leukocytes to inflammatory sites. Several in vivo studies indicate that not only monoclonal antibodies (mAbs) directed against the common beta subunit (CD18) but also to the individual alpha subunits (CD11a, CD11b) can effectively inhibit different types of inflammation. In this study we report that in the adjuvant arthritis (AA) alpha CD11a, alpha CD11b, or even alpha CD18 treatment could not prevent disease development. Moreover, we examined the same mAbs in an acute nonspecific inflammation at different sites in the rat. We found that pretreatment with alpha CD11a or alpha CD11b could significantly block a zymosan peritonitis, but appeared to have no effect on a locally induced joint or dermal inflammation. Interestingly, alpha CD18 treatment, which blocks the entire CD11/CD18 complex, was able to inhibit the influx of inflammatory cells in a peritonitis as well as in a joint and dermal inflammation. These data not only indicate that the type of joint inflammation determines which adhesion molecules play a role in transendothelial migration, but also that involvement of the beta 2 integrins is highly site specific.

Animals↗
PubMed1996

What Models of Granulomatous Inflammation Provide the Immunologist

Granulomas usually serve to protect the host from the spread of persistent microorganisms or other enduring injurious substances. They are complex inflammatory reactions that use many immune mechanisms to control the inciting nudis. These lesions can persist for weeks, months, or even years. Thus, understanding the mechanisms that enhance, diminish, or modulate granulomas could aid in the treatment of many diseases. Moreover, experimental animal models of granulomatous inflammation allow sophisticated investigation of some disease processes not possible using human subjects. Granulomatous inflammations are chronic, composed of activated leukocytes that are selected for deposition at the site of injury. They use various effector mechanisms, delicately balanced by many immunoregulatory circuits. Under some experimental conditions, granulomas can be isolated readily from host tissue and subjected to sophisticated immunological analysis. Therefore, it is possible to dissect the actual, local control mechanisms that govern the granulomatous response. Lesions learned studying granulomas are applicable to other types of inflammation, since granulomas use immunoregulatory networks and soluble cytokines common to many inflammatory states. Using these experimental models, it is readily apparent that studies utilizing splenocytes or peripheral blood leukocytes may not reveal the true, dominant immunoregulatory mechanisms employed at sites of active inflammation. The leukocytes of spleens and blood are a mixture of cells in various stages of activation, many of which are not destined to participate in a selective immune response. Also, granulomas are sustained inflammatory reactions permitting analysis of the unique features of chronic maintenance, as opposed to acute phase inflammation.

Journal Article↗
PubMed1996

Effect of interferon therapy on bile duct inflammation in hepatitis C.

Inflammation of the bile ducts was studied in liver biopsies from patients with chronic hepatitis C to determine whether the frequency of inflamed bile ducts changes with therapy and correlates with other histological variables and expression of class I and II MHC antigens on ductal epithelium. Twenty patients treated at UMMC between 1991 and 1994 underwent needle biopsies of the liver before and after therapy with interferon alpha 2B (IFN). A complete response to therapy was defined as a return to normal serum alanine aminotransferase levels occurring and persisting during therapy. The number of inflamed bile ducts/total ducts (%IBDs), presence of piecemeal necrosis and lymphoid aggregates, and grade of inflammation were assessed in each high-power field in all areas with bile ducts. The frequencies of these variables were compared in cirrhotics and non-cirrhotics and in patients with complete or incomplete responses to IFN. Frozen sections of biopsies from 5 patients were immunostained using antibodies to HLA-DR and B-2 microglobulin, and positive staining was noted on bile ducts. Before therapy, the %IBD was slightly greater in patients with cirrhosis. After IFN, both %IBD and serum alkaline phosphatase levels decreased in non-cirrhotics who responded to IFN. The change in frequency of IBD with IFN paralleled the changes in the other histological features. No correlation was noted between bile duct inflammation and expression of class I and II antigens. The conclusion is that inflammation of the bile ducts occurs frequently in chronic hepatitis C, correlates with other features of inflammation in the triads, and decreases in response to IFN therapy.

Adult↗
PubMed1988

The relationship between antigen levels and middle ear inflammation in antigen-induced otitis media in the chinchilla.

The relationship between antigen levels in middle ear effusions (MEE) and the degree of middle ear inflammation was studied in an antigen-induced otitis media model, using chinchillas sensitized with human serum albumin (HSA). The degree of middle ear inflammation was evaluated by both tympanometric analysis, and cytological and biochemical analyses of the MEE. Middle ear inflammation develops after HSA challenge with a remarkable decrease in HSA levels in the MEE. This inflammation persists even when HSA levels are no longer detectable in the MEE. These findings show that local challenges with an antigen induce a certain degree of middle ear inflammation, which continues even after complete elimination of the antigen from the middle ear through an immunological defense mechanism.

Acoustic Impedance Tests↗
PubMed1997

Role of substance P in several models of bladder inflammation.

Substance P (SP) is a peptide found in the sensory nervous system which has multiple biologic effects including stimulation of muscle contraction, pain nociception, immune cell functions, plasma extravasation and a constellation of inflammatory effects. Here we investigate the role of SP in several animals models of bladder inflammation. Using the female Lewis rat, inflammation was induced using either xylene, lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (polyIC). Inflammation occurred rapidly (4 h) and was maintained in each model for at least 7 days. Each of these protocols decreased the bladder content of immunoreactive SP by approximately 50%, suggesting enhanced release. There was no change in the urinary frequency of these animals over 3 weeks, suggesting that urinary frequency changes are not mediated by acute inflammation. We also found that the SP receptor (NK1) antagonist, (-)CP96345, was unable to block the inflammation produced by polyIC, suggesting that SP is not an obligatory mediator of immune cell stimulation in this model.

Animals↗