No abstract

Background: 5‐Amino salicylic acid preparations are used in therapy for patients with inflammatory bowel diseases. The bioavailability of these drugs depends on their coating. Aim: To determine whether intraluminal pH is decreased by the presence of inflammation, thereby altering the release of 5‐amino salicylic acid in the intestinal lumen. Methods: Intraluminal gastrointestinal pH was measured by means of a radiotelemetry capsule in 12 healthy controls, in 12 patients with Crohn’s disease (five with active disease), and in 11 patients with ulcerative colitis (seven with active disease). Results: The median gastric pH values in the patient groups (Crohn’s disease 2.4, range 1.5–4.1; ulcerative colitis 1.95, range 1.55–4.4) were significantly higher than those observed in the controls (1.55, range 0.95–2.6). In the small bowel and colonic segments, all the pH values of Crohn’s disease patients were comparable to those of the controls, as were the pH values in the proximal small intestine and in the left colon in patients with ulcerative colitis. However, the latter group had higher pH values in the terminal ileum, the caecum and the right colon. Patients with active disease had comparable median gastrointestinal pH values to patients in remission. Conclusions: The luminal release of 5‐amino salicylic acid might not be inhibited by low pH in patients with active inflammatory bowel diseases. This supports a safe disintegration of the slow release mesalazine preparations even in the presence of severe disease.

Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

Neuroimmune interactions play a critical role in the pathogenesis of asthma. Symptoms like wheezing and cough have been attributed to neural dysregulation, whereas sensitization and the induction of allergic inflammation have been linked with the activity of dendritic cells. Neuropeptides were previously shown to control dendritic cell function in vitro, suggesting interactions between dendritic cells and sensory nerves. Here we characterized the anatomical basis of the interactions between dendritic cells and nerves in the airways of mice and monitored the changes during allergic inflammation. Airway microdissection, whole-mount immunohistology, and confocal microscopy were used for the three-dimensional quantitative mapping of airway nerves and dendritic cells along the main axial pathway of nonsensitized versus ovalbumin-sensitized and -challenged CD11c-enhanced yellow fluorescent protein (CD11c-EYFP) transgenic mice. CD11c-EYFP-positive airway mucosal dendritic cells were contacted by calcitonin gene-related peptide-immunoreactive sensory fibers and their co-localization increased in allergic inflammation. Moreover, protein gene product 9.5-positive neuroepithelial bodies and airway ganglia were associated with dendritic cells. In human airways, human leukocyte antigen DR-positive mucosal dendritic cells were found in the close proximity of sensory nerves and neuroepithelial cells. These results provide morphologic evidence of the interactions between dendritic cells and the neural network of the airways at multiple anatomical sites.

In addition to promoting Th2 inflammation, we now suggest a role for the IL-33/ST2 pathway for the induction of peripheral inflammation and mucus production that causes AHR in the peripheral lung. This mechanism for inducing AHR at distal parts of the lung may be of specific importance as asthma is considered as a small airway disease.