Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves

Background: The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. Methods: Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal H-3-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. Principal Findings: Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or H-3-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments. Conclusion: Enteric nerves are of importance in maintaining the intestinal epithelial barrier.Original Publication:Ove Lundgren, Mats Jodal, Madeleine Jansson, Anders T Ryberg and Lennart Svensson, Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves, 2011, PLOS ONE, (6), 2, 16295.http://dx.doi.org/10.1371/journal.pone.0016295Copyright: Public Library of Science (PLoS)http://www.plos.org

A Genetic Basis of Susceptibility to Acute Pyelonephritis

For unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage.We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription.The results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring

Urinary tract infections in children after renal transplantation

Urinary tract infections (UTI) after pediatric kidney transplantation (KTX) are an important clinical problem and occur in 15–33% of patients. Febrile UTI, whether occurring in the transplanted kidney or the native kidney, should be differentiated from afebrile UTI. The latter may cause significant morbidity and is usually associated with acute graft dysfunction. Risk factors for (febrile) UTI include anatomical, functional, and demographic factors as well as baseline immunosuppression and foreign material, such as catheters and stents. Meticulous surveillance, diagnosis, and treatment of UTI is important to minimize acute morbidity and compromise of long-term graft function. In febrile UTI, parenteral antibiotics are usually indicated, although controlled data are not available. As most data concerning UTI have been accumulated retrospectively, future prospective studies have to be performed to clarify pathogenetic mechanisms and risk factors, improve prophylaxis and treatment, and ultimately optimize long-term renal graft survival

Pathogen Specific, IRF3-Dependent Signaling and Innate Resistance to Human Kidney Infection

The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3−/− mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3−/− mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response

Blood perfusion in osteomyelitis studied with [O-15] water PET in a juvenile porcine model

Abstract Background Osteomyelitis is a serious disease which can be difficult to treat despite properly instituted antibiotic therapy. This appears to be related at least partly to degraded vascularisation in the osteomyelitic (OM) lesions. Studies of perfusion in OM bones are, however, few and not quantitative. Quantitative assessment of perfusion could aid in the selection of therapy. A non-invasive, quantitative way to study perfusion is dynamic [ 15 O]water positron emission tomography (PET). We aim to demonstrate that the method can be used for measuring perfusion in OM lesions and hypothesize that perfusion will be less elevated in OM lesions than in soft tissue (ST) infection. The study comprised 11 juvenile pigs with haematogenous osteomyelitis induced by injection of Staphylococcus aureus into the right femoral artery 1\ua0week before scanning (in one pig, 2\ua0weeks). The pigs were dynamically PET scanned with [ 15 O]water to quantify blood perfusion. OM lesions ( N \u2009=\u200917) in long bones were studied, using the left limb as reference. ST lesions ( N \u2009=\u20098) were studied similarly. Results Perfusion was quantitatively determined. Perfusion was elevated by a factor 1.5 in OM lesions and by a factor 6 in ST lesions. Conclusions Blood perfusion was successfully determined in pathological subacute OM lesions; average perfusion was increased compared to that in a healthy bone, but as hypothesized, the increase was less than in ST lesions, indicating that the infected bone has less perfusion reserve than the infected soft tissue