title: Activation of EGF receptors mediates pulmonary vasoconstriction induced by residual oil fly ash.
abstract: Residual oil fly ash (ROFA) is a constituent of pollutant particles that can produce lung injury and activate protein tyrosine phosphorylation cascade. In this study, we determined whether or not protein tyrosine phosphorylation caused lung injury, and if so, identified critical tyrosinephosphorylated proteins that mediated the injury. ROFA was instilled intratracheally into perfused rabbit lungs and injury responses, including increase in pulmonary artery pressure (Ppa), lung weight gain, as well as release of interleukin (IL)-1beta, IL-6, IL-8, and nitrite/nitrate were measured. ROFA increased Ppa and IL-1beta, but inhibited nitrite/nitrate accumulation. Vanadyl sulfate at concentration equivalent to the amount of vanadium detected in the perfusate of ROFA-treated lungs induced similar changes. ROFA enhanced tyrosine phosphorylation of lung proteins, including a 170-kDa protein, likely the epidermal growth factor (EGF) receptor as shown by immunoprecipitation. Pretreatment with genistein, a tyrosine kinase inhibitor, blocked the increase in Ppa and tyrosine phosphorylation of the 170-kDa protein. Intravascular administration of human EGF increased Ppa, and pretreatment with PD153035, an EGF receptor-specific tyrosine kinase inhibitor, attenuated ROFA-induced pulmonary vasoconstriction. These results indicate that tyrosine phosphorylation of EGF receptors in the lung, possibly as a result of inhibition of protein tyrosine phosphatases, mediates constriction of pulmonary vessels induced by ROFA.
authors.affiliation: National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA. huang.tony@epa.gov
authors.forename: Yuh-Chin T
authors.initials: YC
authors.lastname: Huang
authors.forename: Weidong
authors.initials: W
authors.lastname: Wu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Carter
authors.forename: Robert
authors.initials: R
authors.lastname: Silbajoris
authors.forename: Robert B
authors.initials: RB
authors.lastname: Devlin
authors.forename: James M
authors.initials: JM
authors.lastname: Samet
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D002244:Carbon / Q000633:toxicity*; D060729:Coal Ash; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D052638:Particulate Matter; D010477:Perfusion; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000393:Air Pollutants; D060729:Coal Ash; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D009566:Nitrates; D009573:Nitrites; D052638:Particulate Matter; D011799:Quinazolines; D011994:Recombinant Proteins; D014443:Tyrosine; D004815:Epidermal Growth Factor; D002244:Carbon; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline