Exhaled Nitric Oxide in Specific Inhalation Challenge
ABSTRACT Exhaled nitric oxide (eNO) is a biological mediator in human lungs and can be measured easily in exhaled air. Increasing eNO concentrations after specific inhalation testing (SIT) have been described for subjects with occupational asthma. Nevertheless, interpreting eNO concentrations after SIT is still a challenge because eNO concentrations depend on various confounding factors. In this study, 24 women and 43 men with suspected occupational asthma were examined by a questionnaire, physical examination, routine laboratory testing, skin prick testing (atopy: at least one wheal reaction >3 mm), lung function including methacholine testing, and SIT with various occupational allergens. Exhaled NO was measured before SIT (t0), 2 h (t1) and 20-22 h (t2) afterwards (NIOX Flex, Aerocrine, Sweden). At baseline we observed significantly lower eNO concentrations in smokers than in non-smokers and in non-atopics than in atopics (significant only in SIT non-responders). In the SIT non-responders (n = 45), eNO concentrations showed no change after SIT (t0: 16.0, t1: 12.3, t2: 16.0 ppb). In the SIT responders (n = 22), eNO was elevated significantly at t2 (t0: 22.9, t1: 19.9, t2: 42.0 ppb). In addition to positive responder status and measuring time, missing atopy and exposure to isocyanates were the essential factors leading to increased eNO concentrations. We conclude that the measurements of eNO after SIT may provide valuable information concerning the allergenic status of a patient.
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ABSTRACT: Toluene diisocyanate (TDI), a known human asthmagen, was investigated in skin-sensitized Brown Norway rats for its concentration x time (Cxt)-response relationship on elicitation-based endpoints. The major goal of study was to determine the elicitation inhalation threshold dose in sensitized, re-challenged Brown Norway rats, including the associated variables affecting the dosimetry of inhaled TDI-vapor in rats and as to how these differences can be translated to humans. Attempts were made to duplicate at least some traits of human asthma by using skin-sensitized rats which were subjected to single or multiple inhalation-escalation challenge exposures. Two types of dose-escalation protocols were used to determine the elicitation-threshold Cxt; one used a variable C (Cvar) and constant t (tconst), the other a constant C (Cconst) and variable t (tvar). The selection of the “minimal irritant’ C was based an ancillary pre-studies. Neutrophilic granulocytes (PMNs) in bronchoalveolar lavage fluid (BAL) were considered as the endpoint of choice to integrate the allergic pulmonary inflammation. These were supplemented by physiological measurements characterizing nocturnal asthma-like responses and increased nitric oxide in exhaled breath (eNO). The Cconst x tvar regimen yielded the most conclusive dose-response relationship as long C was high enough to overcome the scrubbing capacity of the upper airways. Based on ancillary pre-studies in naïve rats, the related human-equivalent respiratory tract irritant threshold concentration was estimated to be 0.09 ppm. The respective 8-hour time-adjusted asthma-related human-equivalent threshold Cxt-product (dose), in ‘asthmatic’ rats, was estimated to be 0.003 ppm. Both thresholds are in agreement of the current ACGIH TLV® of TDI and published human evidence. In summary, the findings from this animal model suggest that TDI-induced respiratory allergy is likely to be contingent on two interlinked, sequentially occurring mechanisms: first, dermal sensitizing encounters high enough to cause systemic sensitization. Second, when followed by inhalation exposure(s) high enough to initiate and amplify an allergic airway inflammation, then a progression into asthma may occur. This bioassay requires an in-depth knowledge on respiratory tract dosimetry and irritation of the involved test substance to clearly understand the dosimetry causing C- and/or Cxt-dependent respiratory tract irritation and eventually asthma.Toxicology 05/2014; DOI:10.1016/j.tox.2014.02.006 · 3.75 Impact Factor