Mechanisms of aldehyde-induced bronchial reactivity: role of airway epithelium.
To investigate the relative irritant potencies of inhaled aldehydes, guinea pigs were exposed to formaldehyde or acrolein and specific total pulmonary resistance and bronchial reactivity to intravenous acetylcholine were assessed. The mechanisms associated with these responses were investigated by analyzing morphologic and biochemical changes in airway epithelial cells after in vivo and in vitro exposures. Immediately after exposure to formaldehyde or acrolein, specific resistance increased transiently and returned to control values within 30 to 60 minutes. Bronchial hyperreactivity, assessed by the acetylcholine dose necessary to double resistance, increased and became maximal two to six hours after exposure to at least 9 parts per million2 (ppm) formaldehyde or at least 1 ppm acrolein for two hours. The effect of exposure to 3 ppm formaldehyde for two hours was less than the effect of exposure to 1 ppm formaldehyde for eight hours; thus, extended exposures produced a disproportionate heightening of bronchial reactivity. Bronchial hyperreactivity often persisted for longer than 24 hours. Increases in three bronchoconstrictive eicosanoids, prostaglandin F2 alpha, thromboxane B2, and leukotriene C4, occurred immediately after exposure, whereas an influx of neutrophils into lavage fluid occurred 24 hours later. Histological examination of the tracheal epithelium and lamina propria also demonstrated a lack of inflammatory cell infiltration. Treatment with leukotriene synthesis inhibitors and receptor antagonists inhibited acrolein-induced hyperreactivity, supporting a causal role for these compounds in this response. Acrolein also stimulated eicosanoid release from bovine epithelial cells in culture. However, the profile of metabolites formed differed from that found in lavage fluid after in vivo exposure. Similarly, human airway epithelial cells did not produce cysteinyl leukotriene or thromboxane B2. However, cysteinyl leukotrienes were mitogenic for human airway epithelial cells in a concentration-dependent manner and exhibited a structure-activity relationship; leukotriene C4 was more potent than its sequential metabolites D4 and E4. The potency of leukotriene C4 was striking, stimulating colony-forming efficiency in concentrations as low as 0.01 pM. Together, these findings suggest that environmentally relevant concentrations of aldehydes can induce bronchial hyperreactivity in guinea pigs through a mechanism involving injury to cells present in the airways during exposure (rather than from subsequently recruited migratory cells) and that this response is dependent on leukotriene biosynthesis.
Leikauf
G D
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Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0182.
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000171:Acrolein / Q000633:toxicity*; D000393:Air Pollutants / Q000633:toxicity*; D000403:Airway Resistance / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004848:Epithelium / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005557:Formaldehyde / Q000633:toxicity*; D006168:Guinea Pigs; D006965:Hyperplasia; D007249:Inflammation; D007958:Leukocyte Count; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009504:Neutrophils / Q000737:chemistry / Q000378:metabolism; D010640:Phenothiazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011460:Prostaglandins F / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D013189:SRS-A / Q000037:antagonists & inhibitors; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors
D000393:Air Pollutants; D016859:Lipoxygenase Inhibitors; D010640:Phenothiazines; D010654:Phenylbutyrates; D011460:Prostaglandins F; D013189:SRS-A; D005557:Formaldehyde; D007975:Leukotriene B4; D013929:Thromboxane B2; D000171:Acrolein; C050033:L 649923; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; D011464:Epoprostenol; D000109:Acetylcholine; C035296:piriprost