Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner.

The microenvironment of the lung in asthma is acidic, yet the effect of acidity on inflammatory cells has not been well established. We now demonstrate that acidity inhibits eosinophil apoptosis and increases cellular viability in a dose-dependent manner between pH 7.5 and 6.0. Notably, acidity induced eosinophil cyclic adenosine 5'-monophosphate (cAMP) production and enhanced cellular viability in an adenylate cyclase-dependent manner. Furthermore, we identify G protein-coupled receptor 65 (GPR65) as the chief acid-sensing receptor expressed by eosinophils, as GPR65-deficient eosinophils were resistant to acid-induced eosinophil cAMP production and enhanced viability. Notably, GPR65(-/-) mice had attenuated airway eosinophilia and increased apoptosis in 2 distinct models of allergic airway disease. We conclude that eosinophil viability is increased in acidic microenvironments in a cAMP- and GPR65-dependent manner.

Bone marrow cell derived arginase I is the major source of allergen-induced lung arginase but is not required for airway hyperresponsiveness, remodeling and lung inflammatory responses in mice.

BACKGROUND: Arginase is significantly upregulated in the lungs in murine models of asthma, as well as in human asthma, but its role in allergic airway inflammation has not been fully elucidated in mice. RESULTS: In order to test the hypothesis that arginase has a role in allergic airway inflammation we generated arginase I-deficient bone marrow (BM) chimeric mice. Following transfer of arginase I-deficient BM into irradiated recipient mice, arginase I expression was not required for hematopoietic reconstitution and baseline immunity. Arginase I deficiency in bone marrow-derived cells decreased allergen-induced lung arginase by 85.8 +/- 5.6%. In contrast, arginase II-deficient mice had increased lung arginase activity following allergen challenge to a similar level to wild type mice. BM-derived arginase I was not required for allergen-elicited sensitization, recruitment of inflammatory cells in the lung, and proliferation of cells. Furthermore, allergen-induced airway hyperresponsiveness and collagen deposition were similar in arginase-deficient and wild type mice. Additionally, arginase II-deficient mice respond similarly to their control wild type mice with allergen-induced inflammation, airway hyperresponsiveness, proliferation and collagen deposition. CONCLUSION: Bone marrow cell derived arginase I is the predominant source of allergen-induced lung arginase but is not required for allergen-induced inflammation, airway hyperresponsiveness or collagen deposition.

Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.

BACKGROUND: Eosinophilic esophagitis (EE) is a gastrointestinal disorder that is increasingly diagnosed in pediatric patients. OBJECTIVE: We aimed to define, in pediatric patients with EE, their demographic and atopic characteristics, the histopathology of all segments of the gastrointestinal tract, and the effect of therapeutic interventions on the natural history. METHODS: We conducted a retrospective analysis of a database of pediatric patients with EE followed over a period of 8 years. RESULTS: In 89 pediatric patients with EE, male sex (78.6%), white race (94.4%), young age at diagnosis, mean +/- SD, 6.2 +/- 4.8 years, and atopy with sensitization to environmental and food allergens in 79% and 75%, respectively, were prevalent. Patients had EE of the proximal and distal esophagus, and 77% had in addition either mucosal eosinophilia or noneosinophilic histopathology in the stomach, duodenum, and colon. EE was chronic, with a duration of mean +/- SD, 0.91 +/- 0.84 years, until first resolution, and was recurrent; of 66% of the patients who had resolution, 79% later relapsed. CONCLUSION: Eosinophilic esophagitis in the pediatric population is a chronic and relapsing condition, associated with atopy and sometimes with subsequent histopathology in segments of the gastrointestinal tract other than the esophagus. CLINICAL IMPLICATIONS: Physicians evaluating pediatric patients with chronic gastrointestinal symptoms should consider the diagnosis of EE, particularly in young white male patients with atopy. Once diagnosed and treated, the physicians should follow the patients over a period of several years because the course of the disease is protracted, other gastrointestinal segments may be affected, and relapses are common.