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 mu g/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 suggested 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, Cosegregation analyses also suggested that there was no relationship between PAF-induced hyperreactivity and hyperpermeability. There was also no apparent mechanistic relationship between PAF-induced hyperreactivity and basal ACh reactivity based on cosegregation analysis.