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Role of Eosinophils and TNFa after Ozone Inhalation.\nIntroduction: Exposure to ozone induces deleterious responses\nin the airways that include shortness of breath,\ninflammation, and bronchoconstriction. People\nwith asthma have increased airway sensitivity to\nozone and other irritants. Dr. Allison Fryer and\ncolleagues addressed how exposure to ozone affects\nthe immune and physiological responses in\nguinea pigs. Guinea pigs are considered a useful\nanimal model for studies of respiratory and physiological\nresponses in humans; their response to\nairborne allergens is similar to that in humans and\nshares some features of allergic asthma.\nFryer and colleagues had previously observed\nthat within 24 hours of exposure, ozone not only\ninduced bronchoconstriction but also stimulated\nthe production of new cells in the bone marrow,\nwhere all white blood cells develop. As a result\nof ozone exposure, increased numbers of newly\nsynthesized white blood cells, particularly eosinophils,\nmoved into the blood and lungs.\nThe central hypothesis of the current study was\nthat newly synthesized eosinophils recruited to\nthe lungs 3 days after ozone exposure were beneficial\nto the animals because they reduced ozoneinduced\nbronchoconstriction. The investigators\nalso hypothesized that the beneficial effect seen\nin normal (nonsensitized) animals was lost in animals\nthat had been injected with an allergen, ovalbumin\n(sensitized). They also planned to explore\nthe effects of inhibitors of certain cytokines (cellsignaling\nmolecules).\nImmune responses in sensitized animals are\ndominated by a Th2 pattern, which is characterized\nby the synthesis of cytokines (interleukin\n[IL]-4, IL-5, and IL-13) and the Th2 subset of CD4+\nT lymphocytes and the cells they activate (predominantly\neosinophils, and B lymphocytes that\nswitch to making immunoglobulin E [IgE]). Thus,\nsensitized animals were used as a model of allergic\nhumans, whose immune responses tend to be\ndominated by IgE.\nApproach: Fryer and colleagues exposed normal and sensitized\n(allergic) guinea pigs to 2 ppm ozone or filtered\nair for 4 hours and measured changes in cell\nnumbers and airway responses 1 or 3 days later.\nThey counted the numbers of eosinophils and other\nwhite blood cells (macrophages, neutrophils, and\nlymphocytes) in bone marrow, blood, and bronchoalveolar\nlung lavage fluid. The investigators\nalso measured important physiological responses,\nincluding bronchoconstriction. Some animals were\npretreated with etanercept and monoclonal anti-IL-5,\nwhich block tumor necrosis factor-a (TNFa) and IL-5,\nrespectively. TNFa and IL-5 blockers have been used\nto treat patients with asthma.\nA key feature of the study was a technique to distinguish\nwhich white blood cells were synthesized after\nexposure from those that already existed, by injecting\nanimals with bromodeoxyuridine (BrdU). BrdU\nis a thymidine analogue that is incorporated into the\nDNA of dividing cells, serving as a marker of newly\nproduced cells. Therefore, a snapshot can be obtained\nof the proportion of newly synthesized (BrdU-positive)\nversus pre-existing (BrdU-negative) cell types.\nKey results: 1. Allergic and normal animals differed in the time\ncourse of bronchoconstriction and changes in cell\ntypes after ozone exposure. In normal animals,\nbronchoconstriction increased substantially at\nday 1 but decreased by day 3 after ozone exposure.\nIn contrast, in allergic animals bronchoconstriction\nremained high at day 3. Ozone also increased\nthe percentage of newly formed, BrdU2\npositive eosinophils in the bone marrow and\nlungs of normal but not allergic animals.\n2. Pretreatment with the TNFa blocker etanercept\nhad complex effects, which differed between\nnormal and allergic animals. In normal animals,\netanercept decreased ozone-induced new synthesis\nof eosinophils in the bone marrow and\nblocked eosinophil migration to the lung; it also\nincreased bronchoconstriction at day 3 (relative\nto day 1 without etanercept). In allergic animals,\netanercept had no effect on any cell type in the\nbone marrow or lung after exposure to ozone and\ndid not change bronchoconstriction compared\nwith allergic animals not treated with etanercept.\nEtanercept tended to increase the numbers of\nblood monocytes and lymphocytes in air- and\nozone-exposed normal and allergic animals at\nday 3, but had no effect on eosinophils in blood\nat this time point. This was one of the few statistically\nsignificant findings in the blood of exposed\nanimals in the study.\n3. Anti-IL-5 reduced bronchoconstriction at day 3 after\nexposure of allergic animals to ozone. In contrast,\nbronchoconstriction was greatly increased\nin normal animals treated with anti-IL-5.\nConclusions: Fryer and colleagues explored the airway and cellular\nresponses in guinea pigs exposed to ozone. The\nHEI Review Committee, which conducted an independent\nreview of the study, agreed that the findings\nsupported the authors’ hypothesis (1) that exposure\nto ozone stimulates production of eosinophils in bone\nmarrow, (2) that these newly formed eosinophils migrate\nto the lungs, and (3) that those eosinophils play\na delayed but potentially beneficial role in reducing\nozone-induced inflammation in the airways of healthy\nnormal animals, but not in allergen-sensitized animals.\nThe Committee also agreed that guinea pigs\nwere a good model for studying responses to an allergen,\nbecause a major subtype of asthma (the high\nTh2 or allergic type) is associated with high levels of\neosinophils in the blood.\nA novel finding was that the TNFa blocker etanercept\ndecreased ozone-induced formation of eosinophils\nin the bone marrow and blocked eosinophil\nmigration to the lung in normal animals. However,\nbecause injecting etanercept had little effect on eosinophils\nand did not decrease bronchoconstriction in\nallergic guinea pigs, the potential for treating patients\nwith allergic asthma with TNFa blockers is uncertain.\nThis is consistent with the poor performance of TNFa\nblockers in clinical studies of asthma treatment.\nBlocking the cytokine IL-5 with an anti-IL-5 antibody\nsubstantially decreased bronchoconstriction in\nsensitized animals. This suggests that therapies targeting\nIL-5 and eosinophils would be promising in at\nleast some types of asthma. The Committee expressed\ncaution toward experiments with cytokine blockers,\nboth in animal models and humans, because such\nblockers are often not specific to a particular cell type\nand may differ at different sites in the body. Without\nfurther detailed confirmation of the effects of the\nblockers, interpreting these experiments can be challenging.\nThe Committee concluded that the study by Fryer\nand colleagues raises several intriguing directions for\nfuture research, including exploring ways in which\nnewly formed eosinophils differ from pre-existing\nones, and how such findings apply to humans with\nallergy or asthma."}