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Recruitment of Eosinophils to Lungs and Their Role in Vagally Mediated Airway Hyperreactivity Depends upon TNFa and Sensitization Status
Author(s) -
Wicher Sarah A.,
Jacoby David B.,
Fryer Allison D.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.996.5
Subject(s) - sensitization , ovalbumin , eosinophilia , eosinophil , medicine , immunology , bronchoconstriction , tumor necrosis factor alpha , airway resistance , airway , endocrinology , anesthesia , asthma , immune system
Background Fifty‐percent of Americans are routinely exposed to high levels of ozone. Inhaled ozone transiently reduces lung function in healthy individuals, and induces severe exacerbations of airway disease in asthmatics. Since many asthmatics have airway eosinophilia, we evaluated the interaction of ozone and eosinophils in lungs of guinea pigs. We found that eosinophils mediate ozone‐induced airway hyperreactivity 1 day after exposure, but were paradoxically protective against airway hyperreactivity at 3 days. This protective function of eosinophils was lost in guinea pigs with airway eosinophilia induced by ovalbumin sensitization. Objective Since ozone is known to induce tumor necrosis factor‐a (TNFa) production, we characterized the role of TNFa on eosinophil production, function, and migration in non‐sensitized and sensitized guinea pigs exposed to ozone. Methods Non‐sensitized and ovalbumin‐sensitized (4.2 mg i.p., day 1, 3 and 5) guinea pigs were treated with 5‐bromo‐2′‐deoxyuridine (BrdU; 100mg/kg i.p., day 21) to label newly dividing cells. Animals were then exposed to air or ozone (2.0ppm, 4h) and treated with BrdU daily thereafter (50mg/kg i.p.). Some animals were given the TNFa antagonist, etanercept (3mg/kg i.p.) 3 hours before ozone exposure. Three days later, guinea pigs were anesthetized, paralyzed, and ventilated at constant volume and flow. Bronchoconstriction was measured as an increase in pulmonary inflation pressure (mmH 2 0) in response to electrical stimulation of the distal ends of cut vagus nerves (2–25hz, 10V, 0.2msec 5sec on 60sec off). Inflammatory cells were harvested from bone marrow, blood, and lungs. Results Ozone caused eosinophil hematopoiesis in bone marrow, recruited newly divided eosinophils to lungs, and induced airway hyperreactivity to vagal stimulation in non‐sensitized guinea pigs. Sensitization potentiated ozone‐induced airway hyperreactivity, however, eosinophil hematopoiesis and recruitment of newly divided eosinophils to lungs failed to occur. Blocking TNFa inhibited eosinophil hematopoiesis and recruitment to the lungs in non‐sensitized animals, loss of eosinophils further potentiated ozone‐induced airway hyperreactivity. Blocking TNFa had no effects in sensitized guinea pigs exposed to ozone. Conclusions These data demonstrate a novel protective role for eosinophils in vagally‐mediated bronchoconstriction in non‐sensitized animals. In non‐sensitized guinea pigs TNFa mediates ozone induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs where they inhibit vagally mediated bronchoconstriction. These beneficial eosinophils are lost with sensitization. Support or Funding Information Health Effects Institute (ADF), ES017593 (ADF), HL113023 (DBJ), AR061567 (DBJ), HL124165 (DBJ)