Dextran sulfate sodium-induced acute colonic inflammation in angiotensin II type 1a receptor deficient mice

Objective: Angiotensin II (Ang II) receptor blockers have been reported to contribute to cytoprotective effects in various organs. However, the role of renin-angiotensin system (RAS) in modulation of the inflammatory bowel disease (IBD) remains unclear. In this study we assessed the role of angiotensin II type 1a (AT1a) receptor on the outcome of dextran sulfate sodium (DSS)-induced acute colitis by employing AT1a receptor deficient mice. Materials and methods: The acute colitis was induced in wild type (WT) and AT1a receptor deficient mice by giving orally 3% DSS in drinking water for 7 days. Results: Induction of DSS colitis resulted in up-regulation of Ang II and AT1a receptor in the colonic mucosa of WT mice. In parallel, loss of body weight, an increase in disease activity index (DAI), and the shortening of colon were found in DSS-challenged WT mice. In addition, an increase in thiobarbituric acid (TBA)-reactive substances and myeloperoxidase (MPO) activity, along with the up-regulation of tumor necrosis factor (TNF)-α were detected in the colonic mucosa of DSS-challenged WT mice. The endpoints mentioned above were significantly ameliorated in DSS-challenged AT1a receptor deficient mice. Conclusions: RAS is involved in the pathophysiology of DSS-induced colitis and AT1a receptor may be a novel therapeutic target for the treatment of IBD. Received 11 May 2007; returned for revision 12 July 2007; accepted by M. Katori 19 September 2007     

Analysis of toll-like receptor-dependent production of proinflammatory cytokines <Emphasis Type="Italic">in vitro</Emphasis> by human peripheral blood mononuclears of donors and patients with primary immunodeficiency

The production of TNF-α and IFN-α cytokines by peripheral blood mononuclears in response to stimulation by TLR2/6, TLR4, TLR5, TLR9 ligands (zymosan, LPS, flagellin, and CpG-oligodeoxynucleotide, respectively) was studied in donors and patients with common variable immunodeficiency. Individual characteristics of TNF-α production by mononuclears were revealed in donors. Reduced stimulated production of TNF-α in response to stimulation with TLR4 and TLR5 ligands in vitro was detected in patients with common variable immunodeficiency. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 7, pp. 68–71, July, 2007     

Costunolide inhibits production of tumor necrosis factor-α and interleukin-6 by inducing heme oxygenase-1 in RAW264.7 macrophages

Objectives: Heme oxygenase (HO)-1 expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation has an ability to inhibit tumor necrosis factor (TNF)-α and interleukin (IL)-6 production. Costunolide has been reported to inhibit IL-1 production, but whether other cytokines could be inhibited remains to be confirmed. We investigated the effects of costunolide and its components (α-methylene-γ-butyrolactone; CH2-BL, α-methyl-γ-butyrolactone; CH3-BL, and γ-butyrolactone; BL) on HO-1 expression as well as TNF-α and IL-6 production in RAW264.7 macrophages. Methods: HO-1 expression and Nrf2 nuclear accumulation were analyzed by Western blot analysis. The production of TNF-α and IL-6 in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS) was assayed by ELISA. Results: Costunolide and CH2-BL induced HO-1 expression and Nrf2 nuclear accumulation, whereas CH3-BL and BL did not. Pre-incubation with costunolide inhibited LPS-induced production of TNF-α and IL-6. The inhibitory effects of costunolide on TNF-α and IL-6 production were abrogated by tin protoporphyrin, an HO inhibitor. Conclusions: Costunolide is an effective HO-1 inducer capable of inhibiting macrophage-derived pro-inflammatory cytokines. CH2-BL moiety of costunolide is essential for Nrf2 activation leading to HO-1 expression. Received 28 January 2007; returned for revision 4 April 2007; returned for final revision 25 June 2007; accepted by A. Falus 14 July 2007     

Evaluation of Anti-colitic Effect of Lactic Acid Bacteria in Mice by cDNA Microarray Analysis

To evaluate the anti-colitic effect of lactic acid bacteria by cDNA microarray analysis, a lactic acid bacteria mixture (LM) consisting of Lactobacillus brevis HY7401, L. suntoryeus HY7801 and Bifidobacterium longum HY8004 was orally administered to dextran sulfate (DSS)-induced colitic mice and the expression profile of numerous genes was assessed. DSS treatment caused colitic outcomes such as inflammation and colon shortening. DSS also up-regulated the expression of inflammation-related genes: pro-inflammatory and chemotactic cytokines, including IL-1β, TNF-α, IL-6, CCL2, CCL4, CCL7, CCL24, CXCL1, CXCL2, CXCL5, CXCL9 and CXCL10, and their receptors CCR3 and CCR7, and other colitis-related genes such as COX-2, PAP, MMP family, S100a8, S100a9 and DEFA1. LM treatment inhibited the mRNA expression of inflammation-related and tissue remodeling genes induced by DSS as well as the colitic symptoms. LM inhibition for the DSS-induced expression of the representative inflammatory markers, IL-1β, TNF-α and COX-2, was supported by quantitative real-time polymerase chain reaction analysis. These findings suggest that LM ameliorates DSS-induced colitis by regulating inflammatory-related cytokines as well as tissue remodeling genes.     

The Transport Profile of Cytokines in Epidermal Equivalents Subjected to Mechanical Loading

Pressure ulcer risk assessment might be optimized by incorporating the soft tissue reaction to mechanical loading in the currently used risk assessment scales. Cytokines, like IL-1α, IL-1RA, IL-8, and TNF-α, might be used to determine this tissue reaction, since they are released after 24 h of mechanical loading of epidermal equivalents. In the current study, the release and transport of these cytokines with time was evaluated. Epidermal equivalents were subjected to 20 kPa for different time periods (1, 2, 4, 6, 8, 16, and 24 h). Compared to the unloaded control group, a significant increase was found for IL-1α (4.7-fold), IL-1RA (4.8-fold), and IL-8 (3.6-fold) release after 1 h loading. For TNF-α, the release was significantly increased after 4 h of loading (5.1-fold compared to the unloaded situation), coinciding with the first signs of gross structural tissue damage. These cytokine values were determined in the surrounding medium and a transport model was developed to evaluate the distribution of cytokines inside the culture. These simulations revealed that all IL-8 and TNF-α was released from the keratinocytes, whereas most of the IL-1α and IL-1RA remained inside the keratinocytes during the 24 h loading period. In conclusion, IL-1α, IL-1RA, and IL-8 appear promising biochemical markers for pressure ulcer risk assessment, since their release is increased after 1 h of epidermal loading and before the onset of structural tissue damage.     

Rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ, reduces pulmonary inflammatory response in a rat model of endotoxemia

Objective: The effect of rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, on pulmonary inflammation in endotoxemia was investigated. Materials and methods: Male Wistar rats were given either lipopolysaccharide (LPS, 6 mg/kg i.v.) or saline, pretreated with rosiglitazone (0.3 mg/kg i.v.) or its vehicle (dimethyl sulphoxide) 30 min before LPS. The selective PPAR-γ antagonist GW9662 (0.3 mg/kg i.v.) was given 20 min before rosiglitazone. Wet/dry weight (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA) as well as TNF-α and CINC-1 concentrations were measured in lung tissues 4 h after LPS injection. Expression of ICAM-1, NF-κB p65 and PPAR-γ were also determined by immunohistochemistry or Western blot analysis. Results: Rosiglitazone pretreatment significantly attenuated the increases in W/D ratio, MPO activity and MDA levels, and reduced pulmonary overproduction of TNF-α and CINC-1 as well as expression of ICAM-1 following endotoxemia. Rosiglitazone also inhibited the nuclear localization of NF-κB and up-regulated the expression of PPAR-γ protein. The specific PPAR-γ antagonist GW9662 abolished the effect of rosiglitazone. Conclusion: These findings suggest that PPAR-γ agonists might be used as therapeutic agents in the therapy of inflammatory lung injury related to endotoxemia. Received 8 January 2005; returned for revision 6 July 2005; returned for final revision 20 July 2005; accepted by M. Katori 31 July 2005     

PPAR-Gamma Agonist Rosiglitazone Attenuates the Inflammation Caused by Carrageenan in the Mouse Model of Pleurisy

The aim of this study was to investigate the anti-inflammatory efficacy of rosiglitazone (ROSI) in a pleurisy model of carrageenan-induced inflammation. Efficacy was monitored in the mouse pleural cavity by evaluating leukocyte migration, exudate concentration, and myeloperoxidase (MPO) and adenosine deaminase (ADA) activities concomitantly with nitrate/nitrite (NOx), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-17A (IL-17A), and vascular endothelial growth factor-alpha (VEGF-α) levels 4 and 48 h after pleurisy induction. In both phases (4 and 48 h) of pleurisy, ROSI inhibited all the inflammation parameters that were tested (p < 0.05). These results provide evidence that ROSI was efficacious in inhibiting pro-inflammatory mediators. These anti-inflammatory effects are assumed to mainly result from the inhibition of products released from activated leukocytes, such as MPO, ADA, NOx, TNF-α, IL-1β, IL-17A, and VEGF-α.     

Effect and mechanisms of FR167653, a dual inhibitor of TNF-α and IL-1, on BCG plus LPS induced-liver injury

Objective: To investigate the effect of FR167653, a dual inhibitor of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), on Bacillus Calmétte-Guérin (BCG) plus lipopolysaccharide (LPS) induced-liver injury and its mechanisms. Material and methods: Mouse liver injury was established by tail vein injection of 2.5 mg BCG, and 10 d later with 10 μg LPS. The alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed by spectrophotometry. Liver samples were stained with hematoxylin and eosin. Rat hepatocytes (HCs) and Kupffer cells (KCs) were isolated by collagenase IV and pronase perfusion, and purified by density gradient separation. TNF-α and IL-1 concentrations were measured with ELISA. TNF-α and IL-1 mRNA in KCs was analyzed with RT-PCR. Results: FR167653 significantly decreased the elevated transaminase (ALT, AST) activity in serum of liver injured mice. Meanwhile, the degree of inflammatory cell infiltration and liver cell necrosis was also ameliorated. TNF-α and IL-1 production by KCs stimulated with LPS was significantly inhibited by FR167653. RT-PCR analysis demonstrated that FR167653 also reduced the augmented expression of TNF-α and IL-1 mRNA in KCs. However, FR167653 up to 10 μmol/L did not have a toxic effect on KC viability. In addition, FR167653 alleviated the HC injury induced by LPS pre-treated Kupffer cell-conditioned medium (KCCM). Addition of anti-IL-1 and anti-TNF-α MAbs significantly decreased the ALT level released from HCs incubated with LPS or FR167653 pre-treated KCCM. Conclusions: TNF-α and IL-1 released from activated KCs were involved in BCG plus LPS induced liver injury. FR167653 significantly attenuated hepatocyte injury via inhibition of TNF-α and IL-1 released from activated KCs. Hong Wei YAO and Li YUE contributed equally to this work. Received 19 May 2005; returned for revision 11 July 2005; accepted by I. Ahnfelt-R?nne 17 August 2005     

<Emphasis Type="Italic">Ex vivo</Emphasis> production of interferon-γ, tumor necrosis factor-α, and interleukin-6 by mouse macrophages during infection with <Emphasis Type="Italic">M. bovis</Emphasis> and <Emphasis Type="Italic">M. tuberculosis</Emphasis> H37Rv

Ex vivo production of IFN-γ, TNF-α, and IL-6 by mouse peritoneal macrophages was studied during successive infection with the vaccine strain M. bovis BCG and virulent strain M. tuberculosis H37Rv. The increase in the concentrations of TNF-α and IL-6 did not depend on the sequence of macrophage infection with the vaccine or virulent strain, but was related to the presence of the vaccine strain M. bovis BCG in the medium. IFN-γ production depended on infection of macrophages with the virulent strain M. tuberculosis H37Rv. The concentration of IFN-γ was maximum during primary infection with the virulent strain and did not increase after successive infection with the virulent and vaccine strain. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 11, pp. 552–555, November, 2007     

Interleukin-10 and Tumor Necrosis Factor-α Gene Polymorphisms in Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease in humans killing nearly three million people and eight million cases annually. The cytokines TNF-α and IL-10 have been implicated in the pathogenesis of TB. Certain single nucleotide polymorphisms within the promoter region of the IL10 and TNF genes have been associated with altered levels of circulating IL10 and TNF- α. We analyzed TNF-α (−308 G/A, −238 G/A, −376 G/A) and IL10 (−1,082 G/A, −819 C/T, −592 C/A) polymorphisms in 128 patients with TB and 80 healthy subjects using by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). A significant association was found between TB and −1,082 G allele (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41). Significant difference was observed in IL10 GCC and ACC haplotypes distribution between TB and control subjects (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41; Pc: 0.004, O.R 0.53, 95% CI 0.35–0.81). No statistically significant association was found between IL-10 −819 C/T, TNF-α 308 G/A, −238 G/A, −376 G/A polymorphisms, functional TNFα/IL-10 genotypes and TB. Our findings suggest that IL-10 108 2G/A alleles or haplotypes containing these alleles may influence the Th1/Th2 balance and hence may play a role in TB susceptibility and increase risk of developing disease. This polymorphism may be one of the many genetic factors affecting disease outcome.     

Disease modifying effect of statins in dextran sulfate sodium model of mouse colitis

Objective: We evaluated the disease modifying effect of simvastatin and atorvastatin in Dextran Sulfate Sodium (DSS) model of colitis. Materials and methods: Thirty, 8-week old female Swiss-Webster mice were separated into 5 groups (n = 6/group). Colitis was induced by feeding 4 % DSS solution for 7 days. Following discontinuation of DSS, over the next 7 days, the groups orally received simvastatin (20 mg/kg/day), atorvastatin (60 mg/kg/day), vehicle only (0.75 % methylcellulose), subcutaneous 30 μg injections of anti-TNFα monoclonal antibody or intraperitoneal anti-mouse apolipoprotein A-I antibody respectively. Disease activity Index (DAI) was determined daily by a blinded investigator. Results: The mean reduction in DAI scores from day 7 to day 14 for anti-TNFα group, simvastatin and atorvastatin group were 74 %, 76 % and 64 %, respectively as compared to 41 % reduction in vehicle and anti-apolipoprotein A-I antibodytreated groups. Conclusions: This finding suggests that statins may have the ability to modify the disease activity in the DSS model of colitis and the disease modifying effect is comparable to anti-mouse TNFα treatment in this model. Received 23 October 2006; returned for revision 27 February 2007; accepted by I. Ahnfelt-R?nne 16 August 2007     

Lipopolysaccharide-Induced Upregulation of Tumor Necrosis Factor-α (TNF-α) in Rat Spinal Cord

The proinflammatory and lipopolysaccharide (LPS)-inducible cytokine tumor necrosis factor α (TNF-α) has been shown to enhance primary sensory nociceptive signaling. However, the precise cellular sites of TNF-α synthesis is still a matter of controversy. Therefore, we focused our study on TNF-α protein synthesis and expression patterns in spinal cord of controls and rats under systemic challenge with LPS. The Enzyme-linked immunosorbent (ELISA) assay showed that the protein level of TNF-α reached peak at 6 h. Double immunofluorescence revealed that LPS-induced expression of TNF-α exclusively located in a subpopulation of neurons, microglia and macrophages. These observations have demonstrated the production of this proinflammatory cytokine by spinal neurons, but the inherent mechanisms remain unknown. Further studies are needed to confirm the pathogenic role of tumor necrosis factor in the early stage of inflammation. Qin Shen and Dan Zhou contributed equally to this work.     

Isoliquiritigenin, from Dalbergia odorifera, up-regulates anti-inflammatory heme oxygenase-1 expression in RAW264.7 macrophages

Objectives:  Isoliquiritigenin (ISL), one of the major constituents of Dalbergia odorifera T. Chen (Leguminosae), is reported to exert anti-inflammatory effects, but the relevant anti-inflammatory mechanisms are not completely understood. Heme oxygenase-1 (HO-1) has been proven to be involved in the resolution of inflammatory responses. In this study, we investigated whether ISL could induce HO-1 expression in RAW264.7 macrophages, and if so, whether HO-1 could mediate the anti-inflammatory effects of ISL. Methods:  The protein expression of inducible nitric oxide synthase and HO-1 was analyzed by western blot analysis. The production of nitric oxide (NO) and interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) was assayed by Griess and ELISA, respectively. The TNF-α and HO-1 mRNA expression was analyzed by northern blot analysis. Results:  ISL markedly suppressed LPS-induced NO, IL-1β, and TNF-α production. ISL induced HO-1 expression through the extracellular signal-regulated kinase1/2 pathway in RAW264.7 macrophages. The effects of ISL on LPS-induced NO and TNF-α production were reversed by the HO-1 inhibitor, tin protoporphyrin. Conclusions:  ISL is an effective HO-1 inducer capable of inhibiting macrophage-derived inflammation. Received 13 August 2008; returned for revision 15 September 2008; returned for final revision 28 October 2008; accepted by G. Wallace 24 November 2008     

The PPARγ Agonist Rosiglitazone Impairs Colonic Inflammation in Mice with Experimental Colitis

Various animal models showed that peroxisome proliferator-activated receptor (PPAR)γ agonists, when given as a gavage shortly preceding colitis induction, protect against inflammatory bowel disease (IBD). We have examined the effects of 16 days rosiglitazone treatment via the diet prior to dextran sodium sulphate (DSS)-induced colitis in mice. After 7 days DSS in the drinking water, rosiglitazone-fed mice had lost significantly more weight than control mice. Rosiglitazone-treated mice had more diarrhea, weight of colon and spleen were increased, and length of colon was decreased. Histology showed that rosiglitazone-treated mice had more severe colitis, mainly caused by more ulceration, crypt loss, and edema. Immunofluorescence showed a loss of tight junction structure Zonula Occludens protein 1 (ZO-1) in colons of rosiglitazone-treated mice as compared to control mice. Also, serum amyloid P component (SAP) concentrations in plasma were increased. However, concentrations of tumor necrosis factor (TNF)-α and interferon (IFN)-γ in colon homogenates, and TNF-α in spleen homogenates were significantly decreased, whereas interleukin (IL)-10 in spleen homogenates was increased. Other cytokines (IL-2, IL-4, IL-6, IL-12p70 and monocyte chemotactic protein (MCP)-1) and myeloperoxidase (MPO) concentrations showed no differences. In conclusion, 16 days pretreatment with rosiglitazone impaired DSS-induced colitis in mice.     

Protective effect of retinoid against endotoxin-induced mastitis in rats

Objective:  A lipopolysaccharide (LPS) induced mastitis model in rats was used to study the protective effect of retinoid. Materials and methods:  Commencing at gestation day 10, retinoid (dissolved in olive oil) or an equal volume of olive oil was administered to rats daily by gavage until parturition. LPS or pyrogen-free physiological saline was inoculated into the mammary gland 72h after parturition and the rats were euthanized at 12h post-infection. Results:  Myeloperoxidase (MPO), N-acetyl -β-D- glucosaminidase (NAGase), tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8) in mammary tissues and CD4⁺/CD8⁺ in peripheral blood were increased and serum MPO and IL-2 in mammary tissues were decreased 12h after LPS infusion. Retinoid decreased MPO, NAGase, and TNF-α in mammary tissue and increased IL-2 in serum. Four thousand and 8000 I.U/kg•d of retinoid significantly decreased the infiltration of PMNs in mammary alveoli and ameliorated the imbalance of CD4+/CD8+ in peripheral blood. Conclusion:  These results suggest that retinoid protected against LPS-induced mastitis in a rat model. Received 18 March 2008; returned for revision 21 April 2008; received from final revision 22 June 2008; accepted by I. Ahnfeld-R?nne 10 July 2008     

Retinoic Acid Enhances the Production of IL-10 While Reducing the Synthesis of IL-12 and TNF-α from LPS-Stimulated Monocytes/Macrophages

Vitamin A and its metabolites, e.g., all trans-retinoic acid (atRA) and 9-cis-retinoic acid have attracted considerable attention as compounds that have a broad range of immune modulating effects on both humoral and cellular immune responses. The cellular and molecular mechanisms that underlie the effects of retinoids on the immune system remain to be more clearly defined. These immune modulating effects of atRA may be mediated by cytokines elaborated by monocytes and other cell types. To further understand the mechanism(s) by which retinoids affect the immune response, we examined the effects of atRA on several proinflammatory and immune modulating cytokines produced by monocytes. The effects of atRA on LPS-induced mRNA expression of IL-10, IL-12p40, TNF-α, IL-18, and TGF-β in the THP-1 monocyte/macrophage cell line and in cord blood mononuclear cells were measured by competitive RT-PCR. The ELISPOT was employed to evaluate IL-10 and TNF-α protein production enumerating the number of IL-10 and TNF-α producing cells. The addition of atRA to cell cultures potentiated the LPS-induced IL-10 mRNA expression and the number of IL-10 secreting cells from THP-1 cells and cord blood mononuclear cells. In contrast, the addition of atRA inhibited the LPS-induced TNF-α and IL-12p40 mRNA expression, and the number of ELISPOT positive cells for TNF-α. atRA did not change the LPS-induced mRNA expression of IL-18 and TGF-β. These results suggest that atRA may have multiple effects on LPS-induced monocyte/macrophage derived cytokines. While atRA downregulated the proinflammatory cytokines, e.g., IL-12 and TNF-α, the production of an immune modulating cytokine, IL-10 was enhanced by atRA. The effects of atRA on these cytokines may play an important role in the modulation of the immune and inflammatory responses.     

Beneficial effects of cardiac rehabilitation and exercise after percutaneous coronary intervention on hsCRP and inflammatory cytokines in CAD patients

Recent studies showed that tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), as well as high-sensitive C-reactive protein (hsCRP) levels are predictive factors of cardiovascular risk. However, the effect of cardiac rehabilitation (CR) intervention in coronary artery disease (CAD) patients on these factors is not known. The aim of this study was to evaluate the effects of CR and exercise on hsCRP and inflammatory cytokine levels in patients with CAD after percutaneous coronary intervention (PCI). CAD patients who underwent PCI were divided into a CR and exercise group (CRE, n = 29) or a control group (CON, n = 10). CR and exercise consisted of 6 weeks supervised exercise training and 8 weeks home-based, self-managed exercise. Compared to pre-experimental levels, TNF-α (by 20.4%; p = 0.006) and IL-6 (by 49.0%; p < 0.0001), as well as hsCRP (by 59.4%; p < 0.0001), were markedly decreased after CR and exercise in CAD patients but not in control group, except for IL-6 (by 41.6%; p = 0.001). However, there was no significant alteration of adiposity-related variables such as BMI, percent body fat, and waist circumferences, in both groups. We suggest that CR and exercise in CAD patients after PCI induce significant reduction in hsCRP and inflammatory cytokines (TNF-α and IL-6), and marked increase in exercise tolerance and capacity.     

Heat Stress Protects Against Lung Injury in the Neutropenic,Endotoxemic Rat

The objective of this study is to determine if heat stress prior to endotoxemia diminishes cardiopulmonary dysfunction by attenuating the cytokine inflammatory response. Rats were assigned to either: 1) neutropenia; 2) heat; 3) neutropenia, LPS; or 4) heat, neutropenia, LPS. Heart rate, blood gases, and blood, lung lavage, and lung mRNA for tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and macrophage inflammatory protein (MIP)-2 were measured. Heat given before LPS resulted in a similar A-a O₂ gradient as the heat-alone and neutropenic groups (8 ± 8 versus 8 ± 7 versus 4 ± 3 mm Hg) and a lower A-a O₂ gradient when compared to the neutropenic, LPS rats (8 ± 8 versus 22 ± 8 mm Hg, p < 0.003). Blood, lung lavage, and lung mRNA for TNF-α, IL-1β, and MIP-2 were similar in the LPS rats regardless of heat. Heart rate was similar in both LPS groups but higher than non-LPS groups. Heat pretreatment attenuates lung injury in the neutropenic, endotoxemic rat but not by decreasing TNF-α, IL-1β, or MIP-2 in the lung. Heat prior to LPS did not prevent cardiac dysfunction in neutropenic rats.     

Expression profiles of cytokines and chemokines in murine MDR1a-/- colitis

Objective: MDR1a-/- mice spontaneously develop colitis as the result of imperfect epithelial barrier derived from MDR1a deficiency in the large intestine; however, the pathogenesis is not well understood. This study investigated the expression profiles of cytokines and chemokines in murine MDR1a-/- colitis. Methods: MDR1a-/- and wild-type FVB mice were monitored from the 6^th to the 16^th week of age. Production of various cytokines and chemokines in the large intestine and mesenteric lymph node (MLN) cells was examined. Results: Inflammatory cell infiltration, IL-1β production, and MPO activity were aberrantly enhanced in the tissue of MDR1a-/- mice. Under various stimuli, MLN cells produced higher levels of Th1-type (IFN-γ, IL-2, and IL-12) and proinflammatory (IL-1β and TNF-α) cytokines. Inflammatory chemokines MIP-2/CXCL2, KC/CXCL1, MIP-1α/CCL3, MCP-1/CCL2, and RANTES/CCL5 were also markedly upregulated in the tissue. Conclusion: Since the expression profiles of cytokines and chemokines correspond well with those in human IBD, MDR1a-/- mouse is a useful model for the analysis of IBD pathophysiology. Received 12 May 2006; returned for revision vision 15 July 2006; accepted by I. Ahnfelt-R?nne 18 January 2007