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Published on: February 12, 2015
Effects of single and multiple inhalations of platelet-activating factor on airway cell composition and
C D Wegner1, C C Clarke, C A Torcellini
1Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
Abstract:
Platelet-activating factor (PAF) is a potent pro-inflammatory mediator that may play a role in the pathogenesis of airway hyper-responsiveness and asthma. In man, a single inhalation of PAF induces a small but prolonged increase in airway responsiveness in some individuals. The purpose of this study was to determine the effects of single and multiple inhalations of PAF on airway cell composition and responsiveness in monkeys. Anaesthetized and intubated adult male cynomolgus monkeys were studied. Airway cell composition was measured by bronchoalveolar lavage (BAL). Airway responsiveness was measured by determining the concentration (PC100) of inhaled methacholine that caused a 100% increase in respiratory system resistance (Rrs). Airway cell composition (BAL) and responsiveness (PC100) were determined 1 day before and 20 hr after a single inhalation of PAF (approximately 200 micrograms) or 3 days before (Day 0) and 3 days after (Day 10) 3-alternate-day (Days 3, 5 and 7) inhalations of PAF (each approximately 600 micrograms). The single inhalation of PAF (n = 8) caused an acute increase in Rrs (147 +/- 69%), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate (greater than eight fold) in only one animal. The mean +/- s.e. change in log PC100 was -0.29 +/- 0.18. The multiple inhalations of PAF (n = 8) caused acute increases in Rrs (143 +/- 38%, 175 +/- 44% and 156 +/- 39%, respectively), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate in two animals. The mean +/- s.e. change in log PC100 was -0.43 +/- 0.22.
Insights
Platelet-activating factor (PAF) inhalation in monkeys caused airway inflammation and increased responsiveness. Multiple PAF inhalations led to greater airway inflammation and responsiveness changes compared to single doses.
Area of Science:
- Pulmonary Medicine
- Immunology
- Respiratory Physiology
Background:
- Platelet-activating factor (PAF) is a pro-inflammatory mediator implicated in airway hyper-responsiveness and asthma pathogenesis.
- Human studies show single PAF inhalation can cause prolonged airway responsiveness increases in some individuals.
Purpose of the Study:
- To investigate the effects of single and multiple Platelet-activating factor (PAF) inhalations on airway cell composition and responsiveness in cynomolgus monkeys.
Main Methods:
- Airway cell composition was assessed using bronchoalveolar lavage (BAL).
- Airway responsiveness was quantified by measuring the methacholine concentration (PC100) causing a 100% increase in respiratory system resistance (Rrs).
- Measurements were taken before and after single or multiple PAF inhalations.
Main Results:
- Single PAF inhalation induced acute increases in Rrs, elevated BAL granulocytes, and decreased PC100 in some animals.
- Multiple PAF inhalations resulted in significant acute Rrs increases, increased BAL granulocytes, and reduced PC100 in a subset of subjects.
- The decrease in log PC100 was more pronounced with multiple inhalations (-0.43) compared to single inhalation (-0.29).
Conclusions:
- Both single and multiple PAF inhalations can induce airway inflammation and hyper-responsiveness in monkeys.
- Repeated PAF exposure may lead to more significant changes in airway inflammation and responsiveness.
