title: Phosgene- and chlorine-induced acute lung injury in rats: comparison of cardiopulmonary function and biomarkers in exhaled breath.
abstract: This study compares changes in cardiopulmonary function, selected endpoints in exhaled breath, blood, and bronchoalveolar lavage fluid (BAL) following a single, high-level 30-min nose-only exposure of rats to chlorine and phosgene gas. The time-course of lung injury was systematically examined up to 1-day post-exposure with the objective to identify early diagnostic biomarkers suitable to guide countermeasures to accidental exposures. Chlorine, due to its water solubility, penetrates the lung concentration-dependently whereas the poorly water-soluble phosgene reaches the alveolar region without any appreciable extent of airway injury. Cardiopulmonary endpoints were continually recorded by telemetry and barometric plethysmography for 20h. At several time points blood was collected to evaluate evidence of hemoconcentration, changes in hemostasis, and osteopontin. One day post-exposure, protein, osteopontin, and cytodifferentials were determined in BAL. Nitric oxide (eNO) and eCO2 were non-invasively examined in exhaled breath 5 and 24h post-exposure. Chlorine-exposed rats elaborated a reflexively-induced decreased respiratory rate and bradycardia whereas phosgene-exposed rats developed minimal changes in lung function but a similar magnitude of bradycardia. Despite similar initial changes in cardiac function, the phosgene-exposed rats showed different time-course changes of hemoconcentration and lung weights as compared to chlorine-exposed rats. eNO/eCO2 ratios were most affected in chlorine-exposed rats in the absence of any marked time-related changes. This outcome appears to demonstrate that nociceptive reflexes with changes in cardiopulmonary function resemble typical patterns of mixed airway-alveolar irritation in chlorine-exposed rats and alveolar irritation in phosgene-exposed rats. The degree and time-course of pulmonary injury was reflected best by eNO/eCO2 ratios, hemoconcentration, and protein in BAL. Increased fibrin in blood occurred only in chlorine-exposed rats 1-day post-exposure. Hence, the analysis of NO and CO2 in exhaled breath, including endpoints in blood mirroring changes in the peripheral to pulmonary fluid distribution, seem to be sensitive diagnostic endpoints readily available for early prognostic assessment of severity of injury and efficacy of any chosen countermeasure.
authors.affiliation: Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100069, China; Department of Toxicology, Bayer Pharma AG, Wuppertal 42096, Germany.
authors.forename: Sa
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Pharmacology Vascular Diseases, Cardiology & Hematology, Bayer Pharma AG, Wuppertal 42096, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Trübel
authors.affiliation: Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100069, China; Beijing Hospital, Ministry of Health, Beijing 100730, China. Electronic address: cyh-birm@263.net.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Bayer Pharma AG, Wuppertal 42096, Germany; Hannover Medical School, Hannover, Germany. Electronic address: juergen-pauluhn@t-online.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001919:Bradycardia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D001944:Breath Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002245:Carbon Dioxide / Q000378:metabolism*; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D002713:Chlorine / Q000633:toxicity*; D045853:Exhalation; D005740:Gases; D006339:Heart Rate / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects; D019570:Inhalation Exposure / Q000009:adverse effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D053495:Osteopontin / Q000097:blood; D010705:Phosgene / Q000633:toxicity*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D017208:Rats, Wistar; D056152:Respiratory Rate / Q000187:drug effects; D013997:Time Factors
chemical_list: D015415:Biomarkers; D005740:Gases; C506897:Spp1 protein, rat; D053495:Osteopontin; D010705:Phosgene; D002245:Carbon Dioxide; D009569:Nitric Oxide; D002713:Chlorine
keywords: Acute lung injury; Biomarkers in exhaled air; Cardiopulmonary function; Chlorine; Nociceptive sensory reflexes; Phosgene