No abstract

Dysfunction of primary afferents innervating the pancreas has been shown to contribute to the development of painful symptoms during acute and chronic pancreatitis. To investigate the distribution and neurochemical phenotype of pancreatic afferents, Alexa Fluor-conjugated cholera toxin B (CTB) was injected into the pancreatic head (CTB-488) and tail (CTB-555) of adult male mice to label neurons retrogradely in both the dorsal root ganglia (DRG) and nodose ganglia (NG). The NG and DRG (T5–T13) were processed for fluorescent immunohistochemistry and visualized by using confocal microscopy. Spinal pancreatic afferents were observed from T5 to T13, with the greatest contribution coming from T9–T12. The pancreatic afferents were equally distributed between right and left spinal ganglia; however, the innervation from the left NG was significantly greater than from the right. For both spinal and vagal afferents there was significantly greater innervation of the pancreatic head relative to the tail. The total number of retrogradely labeled afferents in the nodose was very similar to the total number of DRG afferents. The neurochemical phenotype of DRG neurons was dominated by transient receptor potential vanilloid 1 (TRPV1)-positive neurons (75%), GDNF family receptor alpha-3 (GFRα3)-positive neurons (67%), and calcitonin gene-related peptide (CGRP)-positive neurons(65%) neurons. In the NG, TRPV1-, GFRα3-, and CGRP-positive neurons constituted only 35%, 1%, and 15% of labeled afferents, respectively. The disparity in peptide and receptor expression between pancreatic afferents in the NG and DRG suggests that even though they contribute a similar number of primary afferents to the pancreas, these two populations may differ in regard to their nociceptive properties and growth factor dependency.

Background: iNOS/NO blocks TNF␣-induced apoptosis by cGMP-dependent and cGMP-independent mechanisms in hepatocytes. Result: TLR4-dependent iNOS expression in hepatocytes leads to NO/cGMP/PKG-dependent TACE/ADAM17 and iRhom2 phosphorylation and interaction, TACE/ADAM17 activation/surface translocation, and TNFR1 shedding. Conclusion: iNOS expression leads to rapid TNFR1 shedding through NO/cGMP/PKG-dependent translocation and activation of TACE/ADAM17. Significance: This novel mechanism for iNOS/NO/cGMP-induced TACE activation and translocation may limit TNF␣-mediated signaling.

Endotoxin-mediated ileus is poorly understood. Our objective was to mechanistically investigate the role of cell-specific TLR4 expression/signaling in causing gastrointestinal dysmotility. TLR4 chimeras and CSF-1-dependent macrophage-deficient mice were subjected to i.p. ultrapure (UP)-LPS (5 mg/kg). At 6 h, gastric emptying and gastrointestinal transit assessed in vivo motility, and jejunal circular muscle contractility was measured in vitro. Muscularis infiltration of neutrophils and monocytes were counted, and intestinal muscularis inflammatory mediators were quantified by quantitative PCR. Demonstrating TLR4 dependency, UP-LPS-induced gastric stasis and ileus of TLR4WT mice were absent in mutant TLR4LPS-d mice. Unexpectedly, engraftment of TLR4-mutant bone marrow into TLR4-competent mice (bmTLR4LPS-d/TLR4WT) exhibited a significant transit delay to UP-LPS similar to bmTLR4WT/TLR4WT mice. CSF-1−/− mice were not protected from ileus. Contrary, UP-LPS-treated bmTLR4WT/TLR4LPS-d and bmTLR4LPS-d/TLR4LPS-d mice had normal transit. No leukocytic infiltration was detected at 6 h. Spontaneous jejunal contractions were markedly suppressed in UP-LPS-treated TLR4-competent mice, but bethanechol-stimulated contractions were not altered by UP-LPS in any group. UP-LPS-induced inflammatory mRNAs in a TLR4-dependent manner, but TLR4 mRNA itself was not significantly altered. In chimera mice, UP-LPS induction of IL-1β and IL-10 were hemopoietic dependent, and GM-CSF was nonhemopoietic dependent, whereas IL-6 and inducible NO synthase were derived from both cell types. Hemopoietic and nonhemopoietic cells contribute to TLR4-sensitive muscularis inflammatory signaling, but nonhemopoietic TLR4 signaling plays an exclusive primary role in causing functional UP-LPS-induced gastric stasis and ileus. Direct LPS suppression of spontaneous contractility participates in mediating early TLR4-transduced dysmotility.

Background and Aims-Early growth response gene-1 (Egr-1) is an important inflammatory transcription factor. We hypothesize that leukocyte-derived Egr-1 plays a key inflammatory role in causing postoperative ileus.

IL10 plays an obligatory role in postoperative intestinal recovery, and exogenous IL10 prevents its development. Pre-emptive exogenous recombinant human IL10 could be a treatment for the prevention of clinical POI.

Rationale Recent studies demonstrate a role for TLR4 in the pathogenesis of pulmonary hypertension (PH), however, the cell types involved in mediating the effects of TLR4 remain unknown. Objectives The objective of this study was to determine the contribution of TLR4 expressed on nonparenchymal cells to the pathogenesis of PH. Methods and Results TLR4 bone marrow chimeric mice revealed an equal contribution of TLR4 on nonparenchymal and parenchymal cells in the pathogenesis of PH as determined by measuring right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). However, deletion of TLR4 from myeloid lineage cells had no effect on the development of PH since we found no difference in RVSP or RVH in WT vs. LysM-TLR4−/− mice. To explore the potential role of platelet TLR4 in the pathogenesis of PH, platelet specific TLR4−/− mice were generated (PF4-TLR4−/− mice). TLR4 −/− platelets from either global TLR4−/− or PF4-TLR4−/− mice were functional but failed to respond to lipopolysaccharide (LPS) demonstrating a lack of TLR4. PF4-TLR4−/− mice demonstrated significant protection from hypoxia-induced PH, including attenuated increases in RVSP and RVH, decreased platelet activation, and less pulmonary vascular remodeling. Deletion of TLR4 from platelets attenuated serotonin release after CH and LPS stimulated platelets released serotonin and promoted pulmonary artery smooth muscle cell proliferation in a serotonin-dependent manner. Conclusions Our data demonstrate that TLR4 on platelets contributes to the pathogenesis of PH and further highlights the role of platelets in PH.

Peng et al. show that human recurrent HSV-2 infection promotes peripheral nerve growth possibly through interactions between IL-17c production by keratinocytes and IL-17RE receptor expression on nerve fibers and sensory neurons. These findings explain the lack of nerve damage during HSV-2 recurrence.