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PubMed2002

Chronic inflammation alters protein metabolism in several organs of adult rats.

Despite the prevalence of chronic inflammatory diseases in developed countries, few studies have considered the metabolic alterations observed in these disorders. To determine which perturbations in protein metabolism occur during chronic inflammation, and the consequences they have on nutritional requirements, a model of ulcerative colitis was adapted for use in adult rats. Adult Sprague-Dawley male rats (9 mo old) received dextran sulfate sodium (DSS) in their drinking water at 50 g/L for 9 d, then at 20 g/L for 18 d. A group of control rats, matched for age and weight, was pair-fed to the treated rats. DSS induced body weight loss and chronic inflammation characterized by an increase of spleen, liver, ileum and colon weights, of blood leukocytes and acute-phase protein levels. The main inflammatory site was the colon, which presented characteristic histological alterations and increased myeloperoxydase activity. Inflammation was accompanied by oxidative stress, characterized by increased plasma protein carbonyl content and increased liver glutathione concentration, but decreased glutathione concentration in muscle. This DSS-induced colitis led to a stimulation of protein synthesis in spleen (+223%), ileum (+40%) and colon (+63%). By contrast, protein synthesis in muscle slowed down (-23%). In conclusion, like acute inflammation, chronic inflammation induced a stimulation of protein metabolism in several splanchnic organs. In muscle, both protein synthesis and degradation were reduced. Taken together, these data are consistent with inadequate amino acid supply to meet the increased requirement resulting from chronic inflammation.

Amino Acids↗
PubMed2003

Association between residual renal function, inflammation and patient survival in new peritoneal dialysis patients.

BACKGROUND: The recent ADEMEX study (Paniagua R, Amato D, Vonesh E et al. J Am Soc Nephrol 2002; 13: 1307-1320) indicates that peritoneal small solute clearance is not as critical for the survival of peritoneal dialysis (PD) patients as thought previously. On the other hand, low residual renal function (RRF), inflammation and an increased peritoneal transport rate (PTR) as evaluated by the peritoneal equilibration test (PET) are reported to be associated with increased mortality in PD patients, but the relationships between these factors and their separate and combined impact on the survival of PD patients are not clear. In this retrospective analysis, we evaluated possible relationships between RRF, inflammation and initial PTR in patients starting PD and the impact of these factors on patient survival. METHODS: A total of 117 patients with initial assessments for RRF, serum C-reactive protein (CRP) and PET at a mean period of 0.4+/-0.2 months (range 0.1-1.0 months) after start of PD were included in this study. Based on RRF (cut-off point, 4 ml/min/1.73 m(2)), serum CRP (cut-off point, 10 mg/l), and the dialysate to plasma creatinine ratio at 4-h of dwell (mean+1 SD), the patients were divided into different groups: low RRF and high RRF group, high CRP and normal CRP group and high PTR and other PTR group, respectively. RESULTS: Of 117 patients, 54 patients (46%) were in low RRF (<4 ml/min/1.73 m(2)) group, 36 patients (31%) were in high serum CRP (> or = 10 mg/l) group and 17 patients (15%) were in high PTR group. Forty-nine patients (42%) had one of these characteristics, 26 patients (22%) had two of these characteristics, two patients (2%) had three, and 40 patients (34%) had none of these characteristics. Patients with low RRF were older and had a higher prevalence of high CRP, lower normalized protein equivalent of total nitrogen appearance (nPNA), lower total Kt/V(urea) and lower total creatinine clearance (CCr) whereas patients with high CRP were older and had a higher proportion of men, lower serum albumin, lower nPNA, lower RRF and lower total CCr. Patients with high PTR had lower serum albumin, higher RRF and higher total CCr compared with patients with other PTR. Upon logistic multiple regression analysis, age and RRF were identified as factors affecting inflammation. Overall patient survival was significantly lower in the patients with low RRF, with high CRP, and in patients with more than two of the following: low RRF, high CRP and high PTR. In contrast, in patients with none of the discriminators low RRF, high CRP and high PTR, the 5-year survival was 100%. A high PTR was associated with decreased survival during the initial year on PD, but not thereafter. Patients who died during the follow-up period had a higher prevalence of high CRP and lower serum albumin, lower RRF, lower Kt/V(urea) and lower total CCr. Upon Cox proportional hazards multivariate analysis, age and RRF were predictors of mortality. CONCLUSIONS: These results indicate that in patients starting PD, low initial RRF is associated with inflammation, and low RRF and inflammation are both associated with high overall mortality. A high PTR was associated with higher mortality, but only during the initial year on PD, whereas Kt/V(urea) did not predict mortality. These results indicate the importance of RRF and inflammation as predictors of mortality in PD patients whereas the predictive power of PTR as such may lose its significance if these two parameters are taken into consideration.

Adult↗
PubMed1999

Subchondral acute inflammation in severe arthritis: a sterile osteomyelitis?

Although arthritis is often associated with synovial inflammation, the osseous changes in inflammatory and degenerative arthritis are principally reactive, and typically lack an acute inflammatory component. We have recently encountered several osteoarticular specimens removed at the time of large joint arthroplasty that have shown a distinctive pattern of subchondral acute inflammation (SCAI) resembling acute bacterial osteomyelitis. These microscopic findings heretofore have not been recognized as a component of the histopathology of arthritis. To determine the frequency of SCAI, we examined slides (mean four per case) from 164 hip arthroplasties performed at one of our institutions in a single year. A total of 10 cases of SCAI, including the 4 original examples (2 humeral head specimens, 2 femoral head specimens) and 6 identified from the slide review are described in this report. Eight patients were female and two were male (ages 54-86 years, mean 70, median 70). All had severe degenerative joint disease, six had rheumatoid arthritis, and three had osteonecrosis. In none was there a clinical or intraoperative suspicion of infection. Cultures of joint fluid or bone were not performed. In all cases, the inflammation was subchondral (within 1.0 cm of the joint surface), and it was frequently associated with subchondral cysts. In osteonecrotic foci, the suppurative inflammation was diffuse within the marrow space, whereas in viable bone it was nodular and vaguely granulomatous. Special stains for organisms were negative. None of the patients was treated with long-term IV antibiotics. There has been no septic loosening of the prostheses at follow-up intervals ranging from 5 to 36 months (mean: 17 months). Our observations, to the best of our knowledge, are novel. Although we cannot definitively exclude bacterial infection as a cause of SCAI, the histologic and clinical features suggest that SCAI likely represents a noninfectious sterile form of inflammation. Subchondral acute inflammation is possibly secondary to synovial fluid insudation into subchondral cancellous bone in the setting of severe osteoarthritis and/or rheumatoid arthritis.

Acute Disease↗
PubMed2001

The anti-inflammatory effects of human recombinant copper-zinc superoxide dismutase on pulp inflammation.

Inflammation in the dental pulp is accompanied by release of a wide variety of highly oxidative molecules known as reactive oxygen species (ROS). ROS concentrations are controlled in vivo by an antioxidant enzyme scavenger system that may be overwhelmed by the increases in ROS production seen during inflammation. Supplementation of the antioxidant defense system, therefore, may limit the severity of the inflammatory response to injury due to this component. To test this hypothesis, this study examined the effects of superoxide radical scavenging on pulpal inflammation induced in rat molars by standardized cavity preparation. The extent of pulp inflammation was compared histomorphometrically between animals treated with exogenous administration of a human recombinant antioxidant enzyme, copper-zinc superoxide dismutase, conjugated to polyethylene glycol (hr-CuZn-SOD), versus saline-vehicle controls. There was a statistically significant reduction in area of inflammation involvement in those animals treated with hrCuZn-SOD, compared with controls. Although hrCuZn-SOD administration did not completely eliminate inflammation in all animals treated, there was a statistically significant lessening of the severity of the inflammatory response, as well as a greater degree of reparative dentin observed in the hrCuZn-SOD-treated animals.

Analysis of Variance↗
PubMed1995

Relationship of interleukin-1 receptor antagonist to mucosal inflammation in inflammatory bowel disease.

Previous work has suggested that the interleukin-1 (IL-1) receptor antagonist, IL-1ra, may regulate mucosal inflammation in inflammatory bowel disease. The present study assessed the relationship of mucosal IL-1ra levels to histologic severity of inflammation and the related proinflammatory cytokines IL-1 beta and IL-6 in children with inflammatory bowel disease. Colonic biopsy specimens from 29 patients with ulcerative colitis, 27 with Crohn's disease, and 24 noninflammatory control subjects were assayed for IL-1ra, IL-1 beta, and IL-6 by enzyme-linked immunosorbent assay. Histologic activity was graded as none, mild, moderate, or severe. Mucosal IL-1 beta levels, but not IL-1ra levels, were significantly elevated in moderate/severely inflamed biopsies from patients with either ulcerative colitis (p < 0.01) or Crohn's disease (p < 0.001) compared with those with none/mild inflammation. The mucosal molar ratio of IL-1ra/IL-1 beta was significantly lower for moderate/severe inflammation compared with none/mild inflammation for patients with ulcerative colitis (p < 0.05) and Crohn's disease (p < 0.01). The mucosal IL-1ra/IL-1 beta ratio was similar in controls to none/mild inflamed biopsies from subjects with either ulcerative colitis or Crohn's disease. Our observations suggest that increasing mucosal inflammation in inflammatory bowel disease in children is associated with a decrease in the "normal" effective IL-1ra/IL-1 beta ratio in which IL-1ra predominates. The importance of this abnormality to the pathogenesis of inflammatory bowel disease awaits further study.

Adolescent↗
PubMed1999

Effect of inflammation on prostatic protein synthesis and luminal secretion in vivo.

PURPOSE: Inflammation of the prostate, or prostatitis, can be caused by an infectious process or can occur in a reportedly non-bacterial form, the etiology of which is largely unknown. The present study was undertaken to establish a method of studying prostatic protein synthesis and secretion in vivo and determine the effects of lipopolysaccharide (LPS)-induced prostatic inflammation on these processes. MATERIALS AND METHODS: Sprague-Dawley rats were divided into three groups: control, 24 hours LPS-inflammation, and 24 hours LPS + antibody against tumor necrosis factor (anti-TNF). 35S-methionine was perifused in vivo around ventral prostate ducts for 3 hours. Ductal fluid (DF) was collected by micropuncture and ductal extract (DE) was collected by tissue homogenization. DE and DF were then subjected to SDS-PAGE and autoradiography. Densitometric analysis of gels and autoradiograms was used to compare protein synthesis (total DE 35S-proteins) and protein secretion (DF 35S-proteins) among the three groups. RESULTS AND CONCLUSIONS: The method proved to be effective for studying prostatic protein synthesis and secretion in vivo. LPS-induced inflammation caused an increase in total 35S-proteins in both the DE and the DF when compared with controls. There were significant increases in both the total number of proteins produced as well as the densitometric quantity of protein in the inflamed group. Some specific prostatic proteins were also upregulated by inflammation. The addition of anti-TNF did not significantly alter inflammation-induced protein synthesis or secretion at the time/dose studied.

Animals↗
PubMed2004

The clinical significance of right-sided colonic inflammation in patients with left-sided chronic ulcerative colitis.

BACKGROUND: Rarely, patchy right colonic inflammation has been observed in patients with left sided chronic ulcerative colitis (CUC), but the clinical significance of this finding is unknown. Therefore, the aim of this study was to evaluate the clinical and pathologic features and natural history of CUC patients with left-sided colitis combined with patchy right colonic inflammation and to compare the clinical course to a control group of patients with isolated left-sided CUC. METHODS: Twelve patients with clinically and pathologically confirmed left-sided CUC, but also with patchy right colonic inflammation, were identified from a cohort of 352 consecutive patients with CUC who underwent colonoscopy at the Brigham and Women's Hospital between 1996 and 2000. In this cohort, 127 patients had left-sided colitis. As the first study to use controls in this setting, 35 consecutive patients with left-sided CUC, but without patchy right colonic inflammation, were selected and evaluated during the same time period. In all patients, the medical records were reviewed for a wide variety of clinical, endoscopic, and pathologic features. The mean follow-up time for the study and control groups was 105 +/- 128 and 112 +/- 80 months, respectively. RESULTS: Patients in the study group were significantly older than the control group at the time of diagnosis (47 +/- 17 years vs 35 +/- 14 years, p = 0.048), but the two groups had a similar gender distribution (25% male vs 40% male), prevalence of extraintestinal manifestations (25% vs 11%), frequency of nonsteroidal anti-inflammatory drug use (75% vs 50%), family history of colitis (27% vs 15%), current tobacco use (8% vs 3%), history of appendectomy (8% vs 0%), and overall severity of disease (33% vs 46%). None of the patients in the study group, and only one control patient, had disease progression to pancolitis. One study patient developed high-grade dysplasia in the rectum that required a colectomy. None of the study or control patients developed clinical or pathologic features of Crohn's disease. CONCLUSIONS: Rarely patients with left-sided CUC may have patchy right colonic inflammation. The clinical features and natural history of patients with left-sided CUC and patchy right colonic inflammation is similar to patients with isolated left-sided CUC.

Adult↗
PubMed2006

Role of adhesion molecules in synovial inflammation.

PURPOSE OF REVIEW: The ability of cells to adhere to other cells and extracellular matrix (ECM) through cellular adhesion molecules (CAMs) is central to tissue remodeling and inflammation. This review discusses the potential role of CAMs in development of synovial inflammation through regulating the recruitment of inflammatory cells via endothelial-leukocyte interactions, the organization and activation of leukocytes in the synovial sublining, and the formation and behavior of the hyperplastic synovial lining. RECENT FINDINGS: Over the past several years valuable insight has been gained into the role of cell-cell and cell-ECM adhesive interactions in synovial organization and inflammation. Recently, cadherin-11 was identified on fibroblast-like synoviocytes and has been demonstrated to play a central role in synovial lining organization. Furthermore, studies using animal models of inflammatory arthritis have demonstrated critical roles for E- and P-selectins, CD11a/CD18 [lymphocyte function-associated antigen (LFA)-1], alpha4beta1 integrin, and cadherin-11 in the development of synovial inflammation. SUMMARY: Cell-cell and cell-ECM interactions through CAMs play an important role in synovial inflammation. Future studies of CAMs are needed to define more thoroughly their role in synovial inflammation and their potential as therapeutic targets in the treatment of rheumatoid arthritis and related inflammatory arthritic conditions.

Animals↗
PubMed2003

Refractory medial conjunctival inflammation associated with jones tubes.

PURPOSE: To report an uncommon complication of refractory medial conjunctival inflammation associated with Jones tubes in 2 patients. METHODS: " Complete ophthalmic and nasal examinations were performed on 2 patients in whom medial conjunctival injection developed after conjunctivodacryocystorhinostomy (cDCR) with Jones tube placement that persisted despite aggressive medical treatment. RESULTS: The medial conjunctival inflammation, which resembled episcleritis, persisted despite removal of the Jones tube in the first patient. The other patient had a "pterygium-like" lesion and ultimately underwent excision of the medial granulation tissue with amniotic membrane graft and exchange of the Jones tube. Histopathologic examination revealed conjunctival tissue with inflammation and fibrosis. CONCLUSIONS: Medial conjunctival inflammation is an uncommon complication of cDCR with Jones tubes. Based on our experience and a thorough review of the literature, medial conjunctival injection and thickening usually resolves once Jones tubes are removed. There have been no previous reports indicating the persistence of medial conjunctival inflammation after Jones tube removal, as was the case in our first patient. These cases suggest that some chronic effect initiated by the Jones tubes and/or surgical manipulation may induce inflammation and scarring of the medial conjunctiva. Multiple surgeries may also predispose to this inflammatory response.

Adult↗
PubMed2005

Neutrophil-mediated inflammation in respiratory syncytial viral bronchiolitis.

BACKGROUND: The involvement of neutrophil-mediated inflammation may play an important role in the pathogenesis of acute respiratory syncytial virus bronchiolitis. However, no measurable marker is sensitive enough to assess neutrophil-mediated inflammation in the airways. Released neutrophil elastase (NE) in intraluminal airways has been reported to induce pulmonary inflammation. The aim of this study was to determine whether the amount of urinary trypsin inhibitor (UTI) in serum, a degenerate induced by NE, reflects the degree of airway inflammation in children with respiratory syncytial viral (RSV) bronchiolitis and whether the severity of inflammation is evaluated. The pre-alpha-/inter-alpha-trypsin inhibitor is assumed to be precursors of the UTI. When NE degrades these inhibitors, UTI is liberated. METHODS: Serum UTI concentrations in infants admitted with RSV bronchiolitis, other viral infections, bacterial pneumonia and control subjects were measured by means of one-step sandwich-type enzyme immunoassay. RESULTS: Serum UTI concentrations in 25 patients on admission were significantly higher than the 15 infantile control values (mean +/- SEM, 22.126 +/- 2.317 and 6.701 +/- 0.719 U/mL, respectively; P < 0.0001). The elevated levels returned to baseline values with improvement in the respiratory symptoms. Higher levels of serum UTI with RSV infection were consistently associated with clinical symptoms and artificial ventilation. Serum NE concentrations of patients were elevated in some patients but not significantly different from controls in the patients who showed only upper respiratory symptoms with RSV infections. CONCLUSION: The findings strongly suggested that neutrophil-mediated events are involved in the pathogenesis of RSV bronchiolitis, and the monitoring of UTI concentrations might be useful for evaluating the neutrophil-mediated airway inflammation.

Bronchiolitis↗
PubMed1993

Acute and chronic phases of unilateral inflammation in rat's ankle are associated with an increase in the proportion of calcitonin gene-related peptide-immunoreactive dorsal root ganglion cells.

Using immunocytochemical methods, the proportion of calcitonin gene-related peptide immunoreactive perikarya was determined in dorsal root ganglia L4-L6 in four control rats and in ten rats with a unilateral inflammation in the ankle region of the left hindlimb. The inflammation was induced by subdermal injection of Freund's complete adjuvant at the ankle. Swelling and cellular infiltration of the ankle region developed within 2 days, and were stable and restricted to the injected ankle for the duration of the 3-week study. In control rats approximately 24% of 20,419 perikarya showed calcitonin gene-related peptide (CGRP)-like immunoreactivity. In rats with unilateral inflammation the proportion of CGRP-positive neurons was increased on the inflamed side to approximately 32% of 11,454 cells at day 2 (P < 0.001 with respect to ganglia in normal rats) and approximately 29% of 10,739 perikarya at day 20 post inoculation (P < 0.01). By contrast, no significant changes were found between ganglia in the non-injected side (approximately 25% at day 2 and approximately 24% at day 20). These results demonstrate that peripheral inflammation is associated with an increase in the proportion of neurons in the dorsal root ganglia that synthetize CGRP. This up-regulation is already present at an early stage of inflammation but also at later stages, suggesting that the increased synthesis of CGRP is an important neurobiological reaction associated with the acute and chronic phases of inflammation.

Acute Disease↗
PubMed2005

Changes in adipocytes and dendritic cells in lymph node containing adipose depots during and after many weeks of mild inflammation.

The time course and cellular basis for inflammation-induced hypertrophy of adipose tissue were investigated over 20 weeks in mature male rats. Mild inflammation was induced by subcutaneous injection of 20 microg lipopolysaccharide into one hind-leg three times/week for 4 or 8 weeks, followed by up to 12 weeks 'rest' without intervention. Mean volume and frequency of apoptosis (TUNEL assay) were measured in adipocytes isolated from sites defined by their anatomical relations to lymph nodes, plus numbers of CCL21-stimulated lymph node-derived and adipose tissue-derived dendritic cells. Experimental inflammation increased dendritic cells and adipocyte apoptosis in the locally stimulated popliteal depot and the lymphoid tissue-associated regions of the contralateral popliteal and mesentery and omentum. Responses declined slowly after inflammation ended, but all measurements from the locally stimulated popliteal depot, and the omentum, were still significantly different from controls after 12 weeks rest. The locally stimulated popliteal adipose tissue enlarged by 5% within 4 weeks and remained larger than the control. We conclude that prolonged inflammation induces permanent enlargement, greater adipocyte turnover and increased dendritic cell surveillance in the adjacent adipose tissue and the omentum. The experiment suggests a mechanism for selective hypertrophy of lymphoid tissue-associated adipose tissue in chronic stress and inflammatory disorders, including impaired lymph drainage, Crohn's disease and HIV-associated lipodystrophy, and a link between evolutionary fitness, sexual selection and aesthetically pleasing body symmetry. It would be useful for further study of molecular mechanisms in inflammation-induced local hypertrophy of adipose tissue and development of specific therapies that avoid interference with whole-body lipid metabolism.

Adipocytes↗
PubMed2005

Blockade of NFkappaB activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney.

BACKGROUND: Transforming growth factor-beta (TGF-beta) in renal fibrosis has been well studied, but little attention has been paid to the potential role of TGF-beta in the resolution of renal inflammation. We hypothesize that TGF-beta exerts its anti-inflammation properties by stimulating its negative signaling pathway involving Smad7. METHODS: A rat remnant kidney model was treated with a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble (Optison)-mediated system. Smad7 transgene expression within the kidney was tightly controlled by the addition of doxycycline in the daily drinking water. All animals were euthanized at week 4 for examination of inflammatory responses. RESULTS: Real-time polymerase chain reaction (PCR) and immunohistochemistry revealed that gene transfer of Smad7 resulted in a substantial inhibition of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) expression (all P < 0.01 vs. control). This was associated with the attenuation of histology damage, proteinuria, serum creatinine, and an increase in creatinine clearance (all P < 0.05). In addition, overexpression of Smad7 significantly inhibited renal inflammation, including ICAM-1, iNOS, and accumulation of macrophages and T cells in both glomeruli and tubulointerstitium. Furthermore, gene transfer of Smad7 also substantially blocked nuclear factor kappa B (NFkappaB) activation in the rat remnant kidney (P < 0.01). CONCLUSION: TGF-beta/Smad7 signaling plays a critical role in the resolution of renal inflammation in rat remnant kidney model. Inhibition of NFkappaB activation is a key mechanism by which Smad7 suppresses renal inflammation, which suggests a crosstalk pathway between NFkappaB and Smad7. The ability of Smad7 to inhibit renal inflammation indicates that ultrasound-microbubble-mediated Smad7 gene therapy may represents a new therapeutic strategy for glomerulonephritis.

Animals↗
PubMed1999

Chronic gastrointestinal inflammation.

Chronic gastrointestinal inflammation is one of the most common types of inflammatory process which affects humans. It is diverse in aetiology, pathogenesis and manifestation. There are also features of chronic inflammation at different sites within the gastrointestinal tract which provide a common thread in terms of the approaches which may be used in investigating these intriguing processes. This paper provides an overview of the mucosal changes in chronic gastrointestinal inflammation. Conserved and variable features of inflammation at different sites extending from the oral cavity to the rectum are highlighted. The involvement of different inflammatory cell types within any diagnostic entity is considered and the progression from an acute to chronic inflammatory condition explored. Important issues in the maintenance of a chronic inflammatory state are the balance between pro- and anti-inflammatory pressures, the driving force behind the inflammation and immune response that is occurring and the mechanisms for curtailment of unwanted or harmful responses which may damage the host. Thus inflammation is likely to result when there is persistence of a driving force and/or imbalance in the pro- and anti-inflammatory mechanisms in the tissue involved.

Animals↗
PubMed2006

A latex-induced allergic airway inflammation model in mice.

Latex allergy is important due to serious health impacts and widespread use of its products. Latex allergic reactions can be induced in skin and mucosal surfaces including the respiratory tract. The development of murine models of allergic airway inflammation has provided a framework to dissect out the cellular and molecular mechanisms of allergic respiratory inflammation. In this study we have developed a new mouse model of latex allergic airway inflammation using aerosol inhalation. The allergic inflammatory responses were characterized in this model. Mice were injected intraperitoneally with 0, 10, 50, or 200 microg of latex extract and their serum anti-latex IgE titers were determined. In the second stage, a standard protocol of inhalation was designed and three doses of latex extract solutions including 1%, 0.1%, and 0.01% were used to induce allergic airway inflammation. Bronchoalveolar lavage cytokines (IL-5 and IL-13) and serum anti-latex IgE and IgG(1) titers were determined by ELISA. Eosinophil levels in lung, peripheral blood, bronchoalveolar lavage and bone marrow were also evaluated. Histological analysis of lung tissue was also performed after latex inhalation. The aerosol inhalation of 1% latex allergens solution and presensitization with 50 mug of latex in this study resulted in the development of allergic airway inflammation characterized by elevated allergen specific IgE and IgG(1), peripheral blood, bronchoalveolar lavage and bone marrow eosinophilia. Histological analysis of the lung revealed an inflammatory response characterized by eosinophil accumulation. Elevated levels of Th2 cytokines IL-5 and IL-13 also were shown in bronchoalveolar lavage samples. These studies demonstrate that sensitization and subsequent aerosol inhalational challenge of latex allergen extract promotes allergic airway inflammation characterized by elevated IL-5 and IL-13 and eosinophils.

Allergens↗
PubMed2006

IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic.

Nuclear factor kappaB (NF-kappaB) is a transcription factor believed to be central in the expression of numerous inflammatory genes and the pathogenesis of many respiratory diseases. We have previously demonstrated increased NF-kappaB pathway activation in a steroid-sensitive animal model of lipopolysaccharide (LPS)-driven airway inflammation. It is noteworthy that this phenomenon was not observed in a steroid-insensitive model of elastase-induced inflammation in the rat. The aim of this study was to gather further evidence to suggest that these similar profiles of neutrophilic inflammation can be NF-kappaB-dependent or -independent by determining the impact of an IkappaB kinase-2 (IKK-2) inhibitor, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1). In the LPS model, TPCA-1 blocked the increase in NF-kappaB DNA binding, a marker of NF-kappaB pathway activation. This inhibition was associated with a reduction in inflammatory mediator release [tumor necrosis factor alpha (TNFalpha)/interleukin-1beta (IL-1beta)/matrix metalloproteinase-9 (MMP-9)] and lung inflammatory cell burden (neutrophilia/eosinophilia). These data were paralleled with a steroid and in human cell based assays. In the elastase-driven inflammation model, in which our group has previously failed to measure an increase in NF-kappaB DNA binding, neither TPCA-1 nor the steroid, affected mediator release (IL-1beta/MMP-9) or cellular burden (neutrophilia/lymphomononuclear cells). This is the first study to examine the effect of an IKK-2 inhibitor in well validated models that mimic aspects of the inflammatory lesion evident in diseases such as COPD. In conclusion, we have demonstrated that animal models with similar profiles of airway inflammation can be IKK-2 inhibitor/steroid-sensitive or -insensitive. If both profiles of inflammation exist in the clinic, then this finding is extremely exciting and may lead to greater understanding of disease pathology and the discovery of novel anti-inflammatory targets.

Amides↗
PubMed2004

Inflammation in ankylosing spondylitis: a systematic description of the extent and frequency of acute spinal changes using magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging (MRI) is increasingly used to detect inflammation in the spine of patients with ankylosing spondylitis (AS). OBJECTIVES: To detect differentially the presence and extent of inflammation in the three spinal segments of patients with AS by MRI. METHODS: In 38 patients with active AS, acute spinal lesions were assessed by T(1) weighted, gadolinium enhanced, spin echo MRI (T(1)/Gd-DTPA) and short tau inversion recovery (STIR) sequences. MRI was quantified by the validated scoring system ASspiMRI-a. Acute spinal lesions were detected in the whole spine and in each spinal segment. One vertebral unit (VU) was defined as the region between two virtual lines drawn through the middle of each vertebral body. RESULTS: A greater number of inflammatory spinal lesions were found by the STIR sequence than by Gd-DTPA: inflammation was present in 30.6% of the VUs as assessed by STIR, compared with 26.8% of the same VUs assessed by T(1)/Gd-DTPA. Inflammation was found more commonly in the thoracic spine (TS) than in the cervical (CS) or the lumbar spine (LS) with both techniques. When STIR was used, spinal inflammation in the CS, the TS, and LS was detected in 10/38 (26%), 28/38 (74%), and 9/38 (24%) patients, respectively. The VU T7/8 was found to be the VU most often affected by both techniques (27.8% by T(1)/Gd-DTPA and 34.5% by STIR). CONCLUSIONS: Spinal inflammation is a common manifestation in patients with AS, and appears more frequently in the TS. The scoring system ASspiMRI-a can be used for evaluation of acute spinal changes in AS.

Acute Disease↗
PubMed2006

Toll-like receptor 4 induced FcgammaR expression potentiates early onset of joint inflammation and cartilage destruction during immune complex arthritis: Toll-like receptor 4 largely regulates FcgammaR expression by interleukin 10.

OBJECTIVE: To study the role of Toll-like receptor (TLR)2 and 4 in the onset of joint inflammation and cartilage destruction during immune complex-mediated arthritis (ICA), and its relationship with FcgammaR expression. MATERIALS AND METHODS: ICA was induced in knee joints of TLR2-/- and TLR4-/- mice and their wild-type controls. Joint inflammation and cartilage destruction were measured in the knee joint using histology. mRNA levels were determined in synovial specimens and macrophages using quantitative polymerase chain reaction and cytokine protein levels in synovial washouts using Bioplex. RESULTS: Joint inflammation and cartilage destruction were not different in arthritic TLR2-/- and wild-type mice. By contrast, at day 1 after ICA induction, joint swelling and proteoglycan depletion in knee joints of TLR4-/- mice were considerably lower (inflammation 68-79% and proteoglycan depletion 27-76%) when compared with wild-type controls. Cytokine production at this time point was markedly reduced in TLR4-/- mice (interleukin (IL)1, IL6, macrophage inflammatory chemokine (MIP)-1alpha and keratinocyte-derived chemokine 49%, 72%, 68% and 84%, respectively). In arthritic synovia of TLR4-/- mice, and also after injection of the antigen poly-l-lysine (PLL) lysozyme alone, mRNA levels of FcgammaR, and the FcgammaR regulating cytokine IL10 were considerably lower. Stimulation of peritoneal macrophages with PLL lysozyme up regulated mRNA levels of FcgammaR and IL10, whereas neutralisation by anti-IL10 antibodies largely blocked FcgammaR up regulation. At day 4, joint inflammation and cartilage destruction were comparable in TLR4-/- mice and wild-type controls. CONCLUSION: TLR4 regulates early onset of joint inflammation and cartilage destruction during ICA arthritis by up regulation of FcgammaR expression and enhanced cytokine production. TLR4-mediated up regulation of FcgammaR is largely mediated by IL10.

Animals↗