No abstract

Elevated colonic lumenal serine protease activity of IBS-D patients evokes a PAR-2-mediated colonic epithelial barrier dysfunction and subsequent allodynia in mice, suggesting a novel organic background in the pathogenesis of IBS.

Stress enhances abdominal contractions in response to rectal distension in rats via pathways involving central CRF and intestinal mast cells.

BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). METHODS Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY RESULTS In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.

Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (α1→2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-α, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases. T o secure their colonization and survival, some bacterial intracellular pathogens have evolved tactics to undermine host innate immune responses, including inflammation. Mycobacterium tuberculosis, the causative agent of human tuberculosis, uses multiple mechanisms to survive within its host cellular niches of alveolar macrophages and dendritic cells (DCs). In particular, M. tuberculosis exposes surface lipoglycans at its cell envelope, namely mannose-capped lipoarabinomannans (ManLAMs), which inhibit the production of proinflammatory cytokines IL-12 and TNF-α by LPS-stimulated human DCs (1-3) via binding to the C-type lectin DC-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) (4, 5). DC-SIGN reportedly modulates immune responses to several other pathogens, supporting its important role as an immunomodulatory receptor (6). ManLAMs are complex amphipathic macromolecules with an average molecular weight of 17 kDa that are composed of three domains: (i) a mannosyl-phosphatidyl-myo-inositol (MPI) anchor; (ii) a heteropolysaccharidic core composed of D-mannan and D-arabinan; and (iii) mannose caps consisting of mono, (α1→2)-di-, and (α1→2)-trimannosides (7). MPI anchor fatty acyl appendages induce a supramolecular organization of ManLAMs in aqueous solution, resulting in the formation of a 30-nm spherical structure of ∼450 molecules with the mannose caps exposed at the surface (8). This multivalent supramolecular structure allows multipoint attachment of ManLAMs, via mannose caps, to multimeric DC-SIGN receptors (9, 10) expressed at the surface of DCs, thereby ensuring high-affinity binding to the receptor (8-10) and induction of antiinflammatory activity (1, 2, 7).The strategy used by M. tuberculosis to down-regulate the...