Bronchoconstriction and Eosinophil Recruitment in Guinea Pig Lungs After Platelet Activating Factor Administration

Abstract

Using a forced expiratory maneuver to measure flow volume loops, we evaluated the ability of platelet activating factor (PAF) to induce acute bronchospasm and in histological changes associated with bronchial asthma in guinea pigs. We determined both the dose-response curve and the time course of PAF-induced bronchoconstriction. Eight guinea pigs with weights ranging from 350 to 450 g were anesthetized, tracheotomized, and then paralyzed with gallamine. Baseline pulmonary function tests (PFT) were done. Different doses (25, 50, 100, 200, and 500 ng/kg) of PAF were injected through the jugular vein, and serial PFTs were done at 30 sec, 2, 5, and 20 min after each dose of PAF. Acetylcholine provocation testing was done following the 200 ng/kg dose of PAF. The PFTs included a forced expiratory maneuver, airway opening pressure (PaO), and total lung compliance (TLC). After all PFTs were completed, cell counts were done on fluid obtained from bronchoalveolar lavage (BAL) and the lungs were removed for histological study. Eight other guinea pigs were used as controls. The results showed that with increasing doses of PAF from 25 ng/kg to 200 ng/kg, all lung function parameters, including vital capacity, peak flow, MFEF 75%, MFEF 50%, MFEF 25%, and total lung compliance, gradually decreased. However, a further increase of the dose of PAF up to 500 ng/kg did not result in continued worsening of PFTs. The most severe bronchoconstriction occurred 30 sec after PAF was injected, and it gradually resolved thereafter. PAF injection also induced a severe inflammatory reaction of the airway and lung tissue, characterized by congestion, edema, inflammatory cell (especially lymphocytes and eosinophils) infiltration, and desquamation of bronchial epithelial cells. In conclusion, in the guinea pig model, PAF can induce acute reversible bronchospasm and bronchial hyperreactivity, as well as the typical histological changes of bronchial asthma.

Stem Cell Factor-Induced Airway Hyperreactivity in Allergic and Normal Mice

“…[3][4][5][6][7][8][9] In particular, eosinophils have been reported to be the primary cell associated with induction of bronchial mucosal injury and are thought to participate in bronchial obstruction and airway hyperreactivity. 6,7 However, other cell populations within the lung, such as mast cells, must be considered as important populations that may initiate and directly contribute to airway damage and hyperreactivity. 8,9 Several therapeutic strategies have focused on attenuating airway inflammation, including glucocorticoids, cromolyn sodium, and other agents that nonspecifically affect the response.…”

“…The initial induction of IgE-mediated mast cell degranulation constitutes the primary mechanism that drives the allergic response and lends to both the early and late phase changes in airway physiology. [3][4][5][6][7][8][9] In addition to IgE-mediated mechanisms, it appears that c-kit ligand or stem cell factor (SCF) can directly induce mast cell activation as well as augment the IgE-mediated response. The prolonged activation of local airway mast cell populations by SCF after initial IgE-mediated events may play a significant role in persistent activation leading to a late phase response.…”

Noninvasive Method to Measure Airway Obstruction in Nonanesthetized Allergen-Sensitized and Challenged Mice

“…The correlation demonstrated between MFEF and other pulmonary function values suggests that MFEF is as reliable as the traditional airway resistance to evaluate airway obstruction in experimental animals [11, 12]. …”

“…Thereafter, 25, 50, 75 and 100 µg/kg of acetylcholine (ACh) were given intravenously at 30-min intervals. Pulmonary function tests were done 5 s after each dose of ACh [11, 12]. Before each dose of ACh, the flow volume loop returned to baseline.…”

“…In small experimental animals, in vivo techniques of measuring airway resistance, peak airway opening pressure and maximal forced expiratory maneuver (MFEM) are the most common methods used to measure acute and late-phase bronchoconstriction and BHR [9, 10, 11, 12]. However, all these methods are invasive, technically demanding and time consuming, requiring anesthetization, tracheostomization and ventilation of the animals.…”