Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034186 (pyelonephritis)
 6,144 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mucosal epithelial linings function as physical barriers against microbes. In addition, they participate in the first line of host defence by production of a variety of proinflammatory mediators when exposed to microbes and microbial agents. Here, we use a human urinary tract infection model to demonstrate that organ- and cell-specific innate responses induced by lipopolysaccharides (LPS) present on Gram-negative bacteria correlates with the expression of Toll-like receptor 4 (TLR4). The presence of TLR4 on human bladder epithelial cells enables them to rapidly respond to bacterial infections in vitro and in vivo. In contrast, TLR4 is not expressed on human proximal tubule cells isolated from the renal cortex, which may explain the cortical localization of bacteria in pyelonephritis. TLR4-negative renal epithelial cells, A498, are non-responsive to purified LPS, however, they respond to viable bacteria via a mannose-sensitive attachment-mediated pathway. To identify LPS components recognised by bladder epithelial cells, a bacterial lipid A mutant and LPS of different chemotypes were tested. Full interleukin 8 induction required hexa-acylated lipid A and was decreased by between 50% and 70% in the presence of O-antigen. Taken together, we propose that multiple independent pathways, which are organ- and cell-specifically expressed, mediate bacterial recognition and determine the outcome of innate responses to infection.
 ...
PMID:Induction of innate immune responses by Escherichia coli and purified lipopolysaccharide correlate with organ- and cell-specific expression of Toll-like receptors within the human urinary tract. 1126 Jan 38

The reported requirement of functional Toll-like receptor (TLR)4 for resistance to Gram-negative pyelonephritis prompted us to localize the expression of TLR2 and TLR4 mRNA in the kidney at the cellular level by in situ hybridization. The majority of the constitutive TLR2 and TLR4 mRNA expression was found to be strategically located in the renal epithelial cells. Assuming that the TLR mRNA expression is representative of apical protein expression, this suggests that these cells are able to detect and react with bacteria present in the lumen of the tubules. To gain insight in the regulation of TLR expression during inflammation, we used a model for renal inflammation. Renal inflammation evoked by ischemia markedly enhanced synthesis of TLR2 and TLR4 mRNA in the distal tubular epithelium, the thin limb of Henle's loop, and collecting ducts. The increased renal TLR4 mRNA expression was associated with significant elevation of renal TLR4 protein expression as evaluated by Western blotting. Using RT-PCR, the enhanced TLR2 and TLR4 mRNA expression was shown to be completely dependent on the action of IFN-gamma and TNF-alpha. These results indicate a potential mechanism of increased immunosurveillance during inflammation at the site in which ascending bacteria enter the kidney tissue, i.e., the collecting ducts and the distal part of the nephron.
 ...
PMID:In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. 1180 67

Symptoms of infection and tissue pathology are caused by the host response; not by the microbe per se. The same response is also critical for the defence and is needed to clear infection. It is therefore essential to understand how the host response is activated and to identify the critical effector mechanisms of the defence. We have studied these issues in the urinary tract infection (UTI) model. The symptoms of UTI and the host defence both rely on the so-called 'innate' immune system, making this one of the best characterized human disease models of 'innate immunity. We discuss the critical molecular events that determine whether the host response will be activated by P-fimbriated uropathogenic Escherichia coli as well as factors determining whether the patient develops acute pyelonephritis or asymptomatic bacteriuria. We will describe the glycoconjugate receptors used by the P-fimbriated bacteria adhering to host tissues, the recruitment of TLR4 co-receptors and the signalling pathways that allow progression to symptomatic disease, and discuss how these mechanisms are altered in asymptomatic carriers, presenting the possible genetic basis for unresponsiveness. We have shown that neutrophils are the critical effectors of the host defence and that neutrophil dysfunctions lead to acute pyelonephritis and renal scarring. Here we discuss the mechanisms of neutrophil-mediated, chemokine receptor (CXCR1)-dependent clearance, and the defect in interleukin-8 receptor homolog knock-out (IL-8Rh KO) mice and describe the data linking low CXCR1 expression to recurrent pyelonephritis in man, as well as the information on the genetic basis for low CXCR1 expression in affected patients. Finally, the mechanisms of renal scarring in IL8Rh KO mice will be discussed in relation to human disease. Our studies hold the promise to provide a molecular and genetic explanation for disease susceptibility in some patients with UTI and to offer more precise tools for the diagnosis and therapy of these infections.
 ...
PMID:The 'innate' host response protects and damages the infected urinary tract. 1181 50

Pyelonephritis, in which renal tubular epithelial cells are directly exposed to bacterial component, is a major predisposing cause of renal insufficiency. Although previous studies have suggested C-C chemokines are involved in the pathogenesis, the exact source and mechanisms of the chemokine secretion remain ambiguous. In this study, we evaluated the involvement of Toll-like receptors (TLRs) in C-C chemokine production by mouse primary renal tubular epithelial cells (MTECs). MTECs constitutively expressed mRNA for TLR1, 2, 3, 4, and 6, but not for TLR5 or 9. MTECs also expressed MD-2, CD14, myeloid differentiation factor 88, and Toll receptor-IL-1R domain-containing adapter protein/myeloid differentiation factor 88-adapter-like. Synthetic lipid A and lipoprotein induced monocyte chemoattractant protein 1 (MCP-1) and RANTES production in MTECs, which strictly depend on TLR4 and TLR2, respectively. In contrast, MTECs were refractory to CpG-oligodeoxynucleotide in chemokine production, consistently with the absence of TLR9. LPS-mediated MCP-1 and RANTES production in MTECs was abolished by NF-kappaB inhibition, but unaffected by extracellular signal-regulated kinase inhibition. In LPS-stimulated MTECs, inhibition of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase significantly decreased RANTES, but did not affect MCP-1 mRNA induction. Thus, MTECs have a distinct expression pattern of TLR and secrete C-C chemokines in response to direct stimulation with a set of bacterial components.
 ...
PMID:Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. 1216 29

Renal scarring after pyelonephritis is common in infancy. In this experimental study performed on tissue from 10-d-old infant and 40-d-old pubertal rats, several aspects of the renal innate immune response to a pyelonephritogenic strain of alpha-hemolysin-expressing Escherichia coli were compared. The kidney typically responds to urinary tract infection with release of proinflammatory cytokines, e.g. IL-6. Basal production of IL-6 from 10-d-old renal cortical tissue was approximately 20% of that from 40-d-old tissue. Six-hour incubation in the presence of supernatant from the E. coli culture caused an approximately 15-fold increase of IL-6 release in 10-d-old tissue and a 5-fold increase in 40-d-old tissue. The absolute level of IL-6 release in stimulated tissue was, however, significantly lower at 10 d than at 40 d. Lipopolysaccharide, the most immunogenic component of E. coli, signals via Toll-like receptor 4. Reverse transcriptase PCR performed on outer renal cortex indicated that expression of Toll-like receptor 4 mRNA was similar in both ages. Microdissection studies revealed that Toll-like receptor 4 mRNA was expressed in proximal tubules but not in glomeruli. The exotoxin alpha-hemolysin, expressed by a majority of uropathogenic E. coli isolates, stimulates IL-6 release via an alternative pathway that signals via intracellular calcium oscillations. We conclude that the higher susceptibility to pyelonephritic scarring is unlikely related to immaturity of innate immune system, as measured by cellular release of IL-6. Instead, the underlying mechanisms for pyelonephritic scarring are most likely multifactorial and may be mainly attributed to anatomic immaturity of the urinary tract.
 ...
PMID:Developmental aspects of Escherichia coli-induced innate responses in rat renal epithelial cells. 1284 Jan 57

Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy). In addition, TLR9 has been shown to be involved in antigen-induced immune complex glomerulonephritis and lupus nephritis by regulating humoral and cellular immune responses. TLR are evolutionary conserved regulators of innate and adaptive immune responses. It is likely that TLR are involved in many if not all types of renal inflammation. Here the authors provide an overview on the biology of TLR, summarize the present data on their expression in the kidney, and provide an outlook for the potential roles of TLR in kidney disease.
 ...
PMID:Signaling danger: toll-like receptors and their potential roles in kidney disease. 1503 87

TLR4 plays a central role in resistance to pyelonephritis caused by uropathogenic Escherichia coli (UPEC). It has been suggested that renal tubule epithelial cells expressing TLRs may play a key role in inflammatory disorders and in initiating host defenses. In this study we used an experimental mouse model of ascending urinary tract infection to show that UPEC isolates preferentially adhered to the apical surface of medullary collecting duct (MCD) intercalated cells. UPEC-infected C3H/HeJ (Lps(d)) mice carrying an inactivating mutation of tlr4 failed to clear renal bacteria and exhibited a dramatic slump in proinflammatory mediators as compared with infected wild-type C3H/HeOuJ (Lps(n)) mice. However, the level of expression of the leukocyte chemoattractants MIP-2 and TNF-alpha still remained greater in UPEC-infected than in naive C3H/HeJ (Lps(d)) mice. Using primary cultures of microdissected Lps(n) MCDs that expressed TLR4 and its accessory molecules MD2, MyD88, and CD14, we also show that UPECs stimulated both a TLR4-mediated, MyD88-dependent, TIR domain-containing adaptor-inducing IFN-beta-independent pathway and a TLR4-independent pathway, leading to bipolarized secretion of MIP-2. Stimulation by UPECs of the TLR4-mediated pathway in Lps(n) MCDs leads to the activation of NF-kappaB, and MAPK p38, ERK1/2, and JNK. In addition, UPECs stimulated TLR4-independent signaling by activating a TNF receptor-associated factor 2-apoptosis signal-regulatory kinase 1-JNK pathway. These findings demonstrate that epithelial collecting duct cells are actively involved in the initiation of an immune response via several distinct signaling pathways and suggest that intercalated cells play an active role in the recognition of UPECs colonizing the kidneys.
 ...
PMID:Renal collecting duct epithelial cells react to pyelonephritis-associated Escherichia coli by activating distinct TLR4-dependent and -independent inflammatory pathways. 1698 18

Ascending urinary tract infection (UTI) and pyelonephritis caused by uropathogenic Escherichia coli (UPEC) are very common infections that can cause severe kidney damage. Collecting duct cells, the site of hormonally regulated ion transport and water absorption controlled by vasopressin, are the preferential intrarenal site of bacterial adhesion and initiation of inflammatory response. We investigated the effect of the potent V2 receptor (V2R) agonist deamino-8-D-arginine vasopressin (dDAVP) on the activation of the innate immune response using established and primary cultured collecting duct cells and an experimental model of ascending UTI. dDAVP inhibited Toll-like receptor 4-mediated nuclear factor kappaB activation and chemokine secretion in a V2R-specific manner. The dDAVP-mediated suppression involved activation of protein phosphatase 2A and required an intact cystic fibrosis transmembrane conductance regulator Cl- channel. In vivo infusion of dDAVP induced a marked fall in proinflammatory mediators and neutrophil recruitment, and a dramatic rise in the renal bacterial burden in mice inoculated with UPECs. Conversely, administration of the V2R antagonist SR121463B to UPEC-infected mice stimulated both the local innate response and the antibacterial host defense. These findings evidenced a novel hormonal regulation of innate immune cellular activation and demonstrate that dDAVP is a potent modulator of microbial-induced inflammation in the kidney.
 ...
PMID:Hormonal control of the renal immune response and antibacterial host defense by arginine vasopressin. 1796 4

Diabetics have a higher incidence of urinary tract infection (UTI), are infected with a broader range of uropathogens, and more commonly develop serious UTI sequelae than nondiabetics. To better study UTI in the diabetic host, we created and characterized a murine model of diabetic UTI using the pancreatic islet beta-cell toxin streptozocin in C3H/HeN, C3H/HeJ, and C57BL/6 mouse backgrounds. Intraperitoneal injections of streptozocin were used to initiate diabetes in healthy mouse backgrounds, as defined by consecutive blood glucose levels of >250 mg/dl. UTIs caused by uropathogenic Escherichia coli (UTI89), Klebsiella pneumoniae (TOP52 1721), and Enterococcus faecalis (0852) were studied, and diabetic mice were found to be considerably more susceptible to infection. All three uropathogens produced significantly higher bladder and kidney titers than buffer-treated controls. Uropathogens did not have as large an advantage in the Toll-like receptor 4-defective C3H/HeJ diabetic mouse, arguing that the dramatic increase in colonization seen in C3H/HeN diabetic mice may partially be due to diabetic-induced defects in innate immunity. Competition experiments demonstrated that E. coli had a significant advantage over K. pneumoniae in the bladders of healthy mice and less of an advantage in diabetic bladders. In the kidneys, K. pneumoniae outcompeted E. coli in healthy mice but in diabetic mice E. coli outcompeted K. pneumoniae and caused severe pyelonephritis. Diabetic kidneys contained renal tubules laden with communities of E. coli UTI89 bacteria within an extracellular-matrix material. Diabetic mice also had glucosuria, which may enhance bacterial replication in the urinary tract. These data support that this murine diabetic UTI model is consistent with known characteristics of human diabetic UTI and can provide a powerful tool for dissecting this infection in the multifactorial setting of diabetes.
 ...
PMID:Streptozocin-induced diabetic mouse model of urinary tract infection. 1864 86

Uropathogenic Escherichia coli (UPEC) are the most frequent causes of urinary tract infections and pyelonephritis. Renal medullary collecting duct (MCD) cells are the intrarenal site to which UPEC strains prefer to adhere and initiate an inflammatory response, but the ability of UPEC strains to translocate across impermeant MCD cells has not been demonstrated definitively. Here, several UPEC strains adhered to the apical surface and translocated across confluent murine inner MCD cells grown on filters. UPEC strains expressing cytolytic and vacuolating cytotoxins disrupted the integrity of cell layers, whereas noncytolytic UPEC strains passed through the cell layers without altering tight junctions. Apical-to-basal transcellular translocation was dramatically reduced after extinction of Toll-like receptor 4 (TLR4) and the lipid raft marker caveolin-1 by small interfering RNA. Furthermore, disruption of lipid raft integrity by filipin III and methyl-beta-cyclodextrin significantly reduced both the transcellular translocation of UPEC across murine inner MCD cell layers and the stimulation of proinflammatory mediators. Bacterial translocation was also significantly reduced in primary cultures of TLR4-deficient mouse MCD cells compared with MCD cells from wild-type mice. Benzyl alcohol, an anesthetic that enhances membrane fluidity, favored the recruitment of caveolin-1 in lipid rafts and increased the translocation of UPEC across cultured TLR4-deficient MCD cells. These findings demonstrate that the transcellular translocation of UPEC strains across impermeant layers of MCD cells may occur through lipid rafts via a TLR4-facilitated process.
 ...
PMID:TLR4 facilitates translocation of bacteria across renal collecting duct cells. 1875 56


1 2 3 Next >>