Susceptibility to platelet-activating factor-induced airway hyperreactivity and hyperpermeability: interstrain variation and genetic control.
Platelet-activating factor (PAF) is a proinflammatory mediator known to elicit changes in airway reactivity and vascular permeability, and it may also have a role in the development and progression of acute respiratory distress syndrome and asthma. We have developed a mouse model to test the hypothesis that these traits were controlled by a single gene and were mechanistically related. We further hypothesized that there was a relationship between PAF-induced hyperreactivity and baseline reactivity to acetylcholine (ACh). Among eight inbred strains of mice that exhibited significant interstrain variation in ACh reactivity, intravenous PAF induced 16 to 278% increases in reactivity to ACh (25 micrograms/kg). PAF also elicited 95 to 307% increases in lung permeability as measured by Evans blue extravasation. Both reactivity and permeability changes induced by PAF were blocked by a PAF receptor antagonist (L-659,989). Strain distribution patterns for baseline reactivity to ACh and PAF-induced hyperreactivity and lung permeability were not significantly concordant, and suggest that the variables were not interdependent. Progeny derived from AKR/J (PAF hyperresponsive) and C3H/HeJ (PAF hyporesponsive) mice were characterized for their PAF responsiveness as determined by PAF-induced hyperreactivity and hyperpermeability. The ratios of hyperresponsive and hyporesponsive phenotypes in outcross progeny were compared to those predicted for Mendelian inheritance and assessed for relatedness by chi 2 and cosegregation analyses. Results suggested that PAF-induced hyperreactivity was controlled by a single gene, but PAF-induced hyperpermeability was controlled by a more complicated interaction of factors.(ABSTRACT TRUNCATED AT 250 WORDS)
Longphre
M
M
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Kleeberger
S R
SR
D000109:Acetylcholine / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D005260:Female; D005663:Furans / Q000494:pharmacology; D005796:Genes; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011652:Pulmonary Circulation / Q000187:drug effects*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled
D005663:Furans; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C054893:L 659989; D000109:Acetylcholine