scholarly journals Deletion of neutral endopeptidase exacerbates intestinal inflammation induced by Clostridium difficiletoxin A

2001 ◽  
Vol 281 (2) ◽  
pp. G544-G551 ◽  
Author(s):  
Kimberly S. Kirkwood ◽  
Nigel W. Bunnett ◽  
John Maa ◽  
Ignazio Castagliolo ◽  
Bao Liu ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Fluid Secretion ◽  
Neutral Endopeptidase ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Genetic Deletion ◽  
Neurokinin 1

Toxin A (TxA) of Clostridium difficile induces acute inflammation of the intestine initiated by release of substance P (SP) and activation of the neurokinin-1 receptor. However, the mechanisms that terminate this response are unknown. We determined whether the SP-degrading enzyme neutral endopeptidase (NEP, EC 3.4.24.11 ) terminates TxA-induced enteritis. We used both genetic deletion and pharmacological inhibition of NEP to test this hypothesis. In wild-type mice, instillation of TxA (0.5–5 μg) into ileal loops for 3 h dose dependently increased ileal fluid secretion, stimulated granulocyte transmigration determined by myeloperoxidase activity, and caused histological damage characterized by depletion of enterocytes, edema, and neutrophil accumulation. Deletion of NEP reduced the threshold secretory and inflammatory dose of TxA and exacerbated the inflammatory responses by more than twofold. This exacerbated inflammation was prevented by pretreatment with recombinant NEP. Conversely, pretreatment of wild-type mice with the NEP inhibitor phosphoramidon exacerbated enteritis. Thus NEP terminates enteritis induced by C. difficile TxA, underlying the importance of SP degradation in limiting neurogenic inflammation.

scholarly journals The Capsule Encoding the viaB Locus Reduces Interleukin-17 Expression and Mucosal Innate Responses in the Bovine Intestinal Mucosa during Infection with Salmonella enterica Serotype Typhi

2007 ◽  
Vol 75 (9) ◽  
pp. 4342-4350 ◽  
Author(s):  
Manuela Raffatellu ◽  
Renato L. Santos ◽  
Daniela Chessa ◽  
R. Paul Wilson ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Mouse Model ◽  
Salmonella Enterica ◽  
Intestinal Inflammation ◽  
Fluid Secretion ◽  
Interleukin 17 ◽  
Loop Model ◽  
Wild Type ◽  
Ileal Loop ◽  
Chemokine Production

ABSTRACT The viaB locus contains genes for the biosynthesis and export of the Vi capsular antigen of Salmonella enterica serotype Typhi. Wild-type serotype Typhi induces less CXC chemokine production in tissue culture models than does an isogenic viaB mutant. Here we investigated the in vivo relevance of these observations by determining whether the presence of the viaB region prevents inflammation in two animal models of gastroenteritis. Unlike S. enterica serotype Typhimurium, serotype Typhi or a serotype Typhi viaB mutant did not elicit marked inflammatory changes in the streptomycin-pretreated mouse model. In contrast, infection of bovine ligated ileal loops with a serotype Typhi viaB mutant resulted in more fluid accumulation and higher expression of the chemokine growth-related oncogene alpha (GROα) and interleukin-17 (IL-17) than did infection with the serotype Typhi wild type. There was a marked upregulation of IL-17 expression in both the bovine ligated ileal loop model and the streptomycin-pretreated mouse model, suggesting that this cytokine is an important component of the inflammatory response to infection with Salmonella serotypes. Introduction of the cloned viaB region into serotype Typhimurium resulted in a significant reduction of GROα and IL-17 expression and in reduced fluid secretion. Our data support the idea that the viaB region plays a role in reducing intestinal inflammation in vivo.

TLR-4 pathway mediates the inflammatory response but not bacterial elimination inE. colipneumonia

2005 ◽  
Vol 289 (5) ◽  
pp. L731-L738 ◽  
Author(s):  
Janet S. Lee ◽  
Charles W. Frevert ◽  
Gustavo Matute-Bello ◽  
Mark M. Wurfel ◽  
Venus A. Wong ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Proinflammatory Cytokine ◽  
Inflammatory Responses ◽  
Mutant Mice ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
E Coli ◽  
Cytokine Levels ◽  
Lower Lung ◽  
Different Strains

We examined the role of Toll-like receptor (TLR)-4 in modifying the lung inflammatory response and its effects on the bacterial recovery from the lungs following inhaled Escherichia coli in two different strains of TLR-4 mutant mice that are hyporesponsive to LPS. The C57BL/10ScN( tlr4lps-del) mice containing a deletion mutation in the TLR-4 gene showed lower proinflammatory cytokine levels, lower lung MPO activity, and less parenchymal and peribronchial inflammation compared with the C57BL/10ScSn mice, a related TLR-4 wild-type substrain. However, the C57BL/10ScN( tlr4lps-del) mutant showed lower bacterial recovery in the lungs following inhaled E. coli associated with a rapid but transient increase in air space neutrophil counts at 6 h. In comparison, the C3H/HeJ( tlr4Lps-d) mutant mice containing a Pro712His substitution in TLR-4 demonstrated lower proinflammatory cytokine levels, lower lung MPO activity, and lower neutrophil accumulation in the air spaces but showed no differences in the bacterial burden of inhaled E. coli at 6 h, when compared with the TLR-4 wild-type C3H/HeSnJ mice. Thus two different TLR-4 mutants showed attenuated inflammatory responses in the lungs, but the reduced inflammatory responses were not consistently associated with either improved or impaired bacterial elimination from the lungs. Our findings indicate that the inflammatory response to inhaled E. coli is TLR-4 dependent, but bacterial elimination depends on other factors in addition to TLR-4.

scholarly journals Mice lacking NKCC1 are protected from development of bacteremia and hypothermic sepsis secondary to bacterial pneumonia

2007 ◽  
Vol 204 (6) ◽  
pp. 1383-1393 ◽  
Author(s):  
MyTrang Nguyen ◽  
Amy J. Pace ◽  
Beverly H. Koller
Keyword(s):  
Klebsiella Pneumoniae ◽  
Physiological Response ◽  
Bacterial Pneumonia ◽  
Acute Inflammation ◽  
Inflammatory Responses ◽  
Fluid Secretion ◽  
Specific Inhibition ◽  
Pulmonary System ◽  
Number Of Cells

The contribution of the Na+-K+-Cl− transporter (NKCC1) to fluid in ion transport and fluid secretion in the lung and in other secretory epithelia has been well established. Far less is known concerning the role of this cotransporter in the physiological response of the pulmonary system during acute inflammation. Here we show that mice lacking this transporter are protected against hypothermic sepsis and bacteremia developing as a result of Klebsiella pneumoniae infection in the lung. In contrast, this protection was not observed in NKCC1−/− mice with K. pneumoniae—induced peritonitis. Although overall recruitment of cells to the lungs was not altered, the number of cells present in the airways was increased in the NKCC1−/− animals. Despite this robust inflammatory response, the increase in vascular permeability observed in this acute inflammatory model was attenuated in the NKCC1−/− animals. Our studies suggest that NKCC1 plays a unique and untoward unrecognized role in acute inflammatory responses in the lung and that specific inhibition of this NKCC isoform could be beneficial in treatment of sepsis.

Overlapping Functions of E- and P-Selectin in Neutrophil Recruitment During Acute Inflammation

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2345-2352 ◽  
Author(s):  
Jonathon W. Homeister ◽  
Mengkun Zhang ◽  
Paul S. Frenette ◽  
Richard O. Hynes ◽  
Denisa D. Wagner ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Functional Roles ◽  
Leukocyte Accumulation ◽  
Vascular Bed ◽  
Precise Role ◽  
Wild Type Control

Abstract Selectin adhesion molecules mediate leukocyte rolling on activated endothelium, a prerequisite to leukocyte accumulation at sites of inflammation. The precise role of each selectin (E-, P-, and L-) in this process is unclear and may vary depending on the particular inflammatory stimulus, vascular bed, leukocyte subset, and species; most data suggest discrete functional roles for each selectin. To define the relative roles of E- and P-selectin in mediating neutrophil accumulation in acute dermal inflammation, mice genetically deficient in E-selectin, P-selectin, or both E- and P-selectin were injected intradermally with zymosan. Luminal endothelial expression of E- and P-selectin in response to zymosan was documented in wild-type mice by intravenous administration of fluorochrome-labeled anti–E- and anti–P-selectin antibodies. In mice deficient in E- or P-selectin, neutrophil accumulation was unchanged or only subtly reduced relative to wild-type control mice. In mice deficient in both E- and P-selectin, neutrophil accumulation was significantly reduced (87% at 4 hours and 79% at 8 hours). These data demonstrate that, in this model of acute inflammation, there is considerable overlap in the functions of E- and P-selectin; loss of both selectins was required to impair neutrophil accumulation.

scholarly journals Attaching and Effacing Bacterial Effector NleC Suppresses Epithelial Inflammatory Responses by Inhibiting NF-κB and p38 Mitogen-Activated Protein Kinase Activation

2011 ◽  
Vol 79 (9) ◽  
pp. 3552-3562 ◽  
Author(s):  
Ho Pan Sham ◽  
Stephanie R. Shames ◽  
Matthew A. Croxen ◽  
Caixia Ma ◽  
Justin M. Chan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Mitogen Activated Protein Kinase ◽  
Loop Model ◽  
Wild Type ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
The Impact

ABSTRACTEnteropathogenicEscherichia coli(EPEC) and enterohemorrhagicE. coliare noninvasive attaching and effacing (A/E) bacterial pathogens that cause intestinal inflammation and severe diarrheal disease. These pathogens utilize a type III secretion system to deliver effector proteins into host epithelial cells, modulating diverse cellular functions, including the release of the chemokine interleukin-8 (IL-8). While studies have implicated the effectors NleE (non-locus of enterocyte effacement [LEE]-encoded effector E) and NleH1 in suppressing IL-8 release, by preventing NF-κB nuclear translocation, the impact of these effectors only partially replicates the immunosuppressive actions of wild-type EPEC, suggesting another effector or effectors are involved. Testing an array of EPEC mutants, we identified the non-LEE-encoded effector C (NleC) as also suppressing IL-8 release. Infection by ΔnleCEPEC led to exaggerated IL-8 release from infected Caco-2 and HT-29 epithelial cells. NleC localized to EPEC-induced pedestals, with signaling studies revealing NleC inhibits both NF-κB and p38 mitogen-activated protein kinase (MAPK) activation. UsingCitrobacter rodentium, a mouse-adapted A/E bacterium, we found that ΔnleCand wild-typeC. rodentium-infected mice carried similar pathogen burdens, yet ΔnleCstrain infection led to worsened colitis. Similarly, infection with ΔnleCC. rodentiumin a cecal loop model induced significantly greater chemokine responses than infection with wild-type bacteria. These studies thus advance our understanding of how A/E pathogens subvert host inflammatory responses.

scholarly journals Bleomycin-induced pulmonary injury in mice deficient in SPARC

2000 ◽  
Vol 279 (4) ◽  
pp. L743-L750 ◽  
Author(s):  
Rashmin C. Savani ◽  
Zhao Zhou ◽  
Evguenia Arguiri ◽  
Sunny Wang ◽  
Dinh Vu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Acute Inflammation ◽  
Direct Evidence ◽  
Pulmonary Injury ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
The Matrix ◽  
Chemical Peritonitis ◽  
Deficient Mice ◽  
Wild Type Control

SPARC (secreted protein, acidic and rich in cysteine) is a component of the matrix that appears to regulate tissue remodeling. There is evidence that it accumulates in the lung in the setting of pulmonary injury and fibrosis, but direct evidence of its involvement is only now emerging. We therefore investigated the development of pulmonary fibrosis induced by bleomycin administered either intratracheally or intraperitoneally in mice deficient in SPARC. Bleomycin (0.15 U/mouse) given intratracheally induced significantly more pulmonary fibrosis in mice deficient in SPARC compared with that in wild-type control mice, with the mutant mice demonstrating greater neutrophil accumulation in the lung. However, in wild-type and SPARC-deficient mice given intraperitoneal bleomycin (0.8 U/injection × 5 injections over 14 days), the pattern and severity of pulmonary fibrosis, as well as the levels of leukocyte recruitment, were similar in both strains of mice. These findings suggest that the involvement of SPARC in pulmonary injury is likely to be complex, dependent on several factors including the type, duration, and intensity of the insult. Furthermore, increased neutrophil accumulation in the peritoneal cavity was also observed in SPARC-null mice after acute chemical peritonitis. Together, these data suggest a possible role for SPARC in the recruitment of neutrophils to sites of acute inflammation.

scholarly journals Overlapping Functions of E- and P-Selectin in Neutrophil Recruitment During Acute Inflammation

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2345-2352 ◽  
Author(s):  
Jonathon W. Homeister ◽  
Mengkun Zhang ◽  
Paul S. Frenette ◽  
Richard O. Hynes ◽  
Denisa D. Wagner ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Leukocyte Rolling ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Functional Roles ◽  
Leukocyte Accumulation ◽  
Vascular Bed ◽  
Precise Role ◽  
Wild Type Control

Selectin adhesion molecules mediate leukocyte rolling on activated endothelium, a prerequisite to leukocyte accumulation at sites of inflammation. The precise role of each selectin (E-, P-, and L-) in this process is unclear and may vary depending on the particular inflammatory stimulus, vascular bed, leukocyte subset, and species; most data suggest discrete functional roles for each selectin. To define the relative roles of E- and P-selectin in mediating neutrophil accumulation in acute dermal inflammation, mice genetically deficient in E-selectin, P-selectin, or both E- and P-selectin were injected intradermally with zymosan. Luminal endothelial expression of E- and P-selectin in response to zymosan was documented in wild-type mice by intravenous administration of fluorochrome-labeled anti–E- and anti–P-selectin antibodies. In mice deficient in E- or P-selectin, neutrophil accumulation was unchanged or only subtly reduced relative to wild-type control mice. In mice deficient in both E- and P-selectin, neutrophil accumulation was significantly reduced (87% at 4 hours and 79% at 8 hours). These data demonstrate that, in this model of acute inflammation, there is considerable overlap in the functions of E- and P-selectin; loss of both selectins was required to impair neutrophil accumulation.

scholarly journals Cell adhesion molecule mediation of myocardial inflammatory responses associated with ventricular pacing

2012 ◽  
Vol 302 (7) ◽  
pp. H1387-H1393 ◽  
Author(s):  
Katrina Go Yamazaki ◽  
Sang-Hyun Ihm ◽  
Robert L. Thomas ◽  
David Roth ◽  
Francisco Villarreal
Keyword(s):  
Cell Adhesion ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Left Ventricular ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Vascular Events ◽  
In The Wild

Poorly synchronized activation of the ventricles can lead to impairment of normal cardiac structure/function. We reported previously that short term (4 h) left ventricular (LV) pacing-induced ventricular dyskinesis led to an inflammatory response localized to the epicardium. Results from this study demonstrated that neutrophils may play a major role in this inflammatory process. Neutrophil recruitment to a site of injury is a process that is highly dependent on an upregulation of cell adhesion molecules (CAM). The dependence of ventricular dysynchrony-induced inflammatory responses on CAM upregulation has not been explored. To gain further insight, we used a mouse model of LV pacing to evaluate the role of CAM in mediating the inflammatory response associated with ventricular dyskinesis. We first examined the effects of LV pacing in wild-type mice. Results demonstrate that 40 min of LV pacing increases ICAM-1 immunostaining as well as myeloperoxidase activity and tissue oxidative stress by twofold in early-activated myocardium. Matrix metalloproteinase-9 activity also increased in the same region by ∼3.5-fold. To determine the role of CAM, mice null for ICAM-1 or p-selectin were subjected to 40 min LV pacing. Results demonstrate that the inflammatory response seen in the wild-type mice was significantly mitigated in the ICAM-1 and p-selectin null mice. In conclusion, results demonstrate that CAM expression plays a critical role in the triggering of LV pacing-induced inflammation, thus providing evidence of a vascular mechanism underlying this response. The mechanisms that trigger an upregulation of myocardial CAM expression and, therefore, inflammation await further investigation since they suggest a specific involvement of vascular events.

Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF

2005 ◽  
Vol 289 (2) ◽  
pp. F469-F480 ◽  
Author(s):  
Shenyang Li ◽  
Neriman Gokden ◽  
Mark D. Okusa ◽  
Renu Bhatt ◽  
Didier Portilla
Keyword(s):  
Inflammatory Responses ◽  
Kidney Tissue ◽  
Neutrophil Infiltration ◽  
Binding Activity ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Chemokine Production ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Recently, we demonstrated that peroxisome proliferator-activated receptor-α (PPARα) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990–F998, 2004). In the following studies, we examined the protective effect of PPARα ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-α, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARα ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARα ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARα null mice. In addition, we observed that cisplatin-induced NF-κB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARα ligand. These results demonstrate that PPARα exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-κB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF.

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