PAF‐induced bronchial hyperresponsiveness in the rabbit: contribution of platelets and airway smooth muscle

Abstract

Aerosol administration of platelet activating factor (PAF) to normal rabbits induced an enhanced airway responsiveness to inhaled histamine, 6 and 24 h after exposure. Following exposure to bovine serum albumin (BSA) as the carrier molecule for PAF, there was an increase in airway responsiveness to histamine 6h after challenge, although by 24 h this was not significantly different from the responsiveness of airways to histamine before BSA. PAF‐induced bronchial hyperresponsiveness at 24 h was associated with a substantial increase in the number of neutrophils and mononuclear cells and a small, but significant increase in the number of eosinophils in the lungs as assessed by bronchoalveolar lavage. BSA exposure failed to alter the total number of cells in the lungs, although there was a significant increase in the number of neutrophils in the bronchoalveolar lavage fluid. Selective platelet depletion with a guinea‐pig anti‐rabbit platelet serum inhibited PAF‐induced bronchial hyperresponsiveness. In addition, there was an attenuation of PAF‐induced airway inflammation in animals rendered thrombocytopenic. The contractile potency to histamine, methacholine and carbachol was similar in intrapulmonary bronchi taken from rabbits exposed to an aerosol of BSA or PAF. Furthermore, the relaxant potency to the non‐selective β‐adrenoceptor agonist isoprenaline, was unaltered in PAF‐treated rabbits. In contrast, there was a 2.58 fold reduction in the relaxant potency to theophylline in rabbits exposed to PAF compared with rabbits exposed to BSA. These results suggest that in the rabbit, PAF‐induced bronchial hyperresponsiveness at 24 h is associated with airways inflammation and is dependent upon platelet activation, but is not related to changes in airway smooth muscle function.

Effect of PF 10040 on PAF‐induced airway responses in neonatally immunized rabbits

“…However, this explanation seems unlikely as we were clearly able to inhibit PAF-induced pulmonary cell infiltration and airway hyperresponsiveness with PF 10040. Both of these responses have also been shown previously to be plateletdependent in the rabbit (Coyle et al, 1990), making our present results somewhat surprising. In the present study, PAF aerosol induced airway hyperresponsiveness to inhaled histamine 24 h after challenge.…”

“…The local administration of PF 10040 into rabbit skin has recently been shown to inhibit oedema formation induced by PAF (Rossi et al, 1992) (Hosford et al, 1989) as this biological response induced by PAF is known to be a platelet dependent phenomenon (Coyle et al, 1990). It is plausible that we failed to inhibit PAF-induced bronchoconstriction with PF 10040 because we did not achieve high enough local concentrations of the drug in the airways.…”

Effect of heparin and a low‐molecular weight heparinoid on PAF‐induced airway responses in neonatally immunized rabbits

“…These findings furthermore suggest that the inhibition of PAF-induced airway hyperresponsiveness and cell infiltration by heparin cannot be explained by heparin acting merely as a PAF antagonist. We have previously reported that PAF-induced airway hyperresponsiveness and eosinophil infiltration in the rabbit is platelet dependent, being substantially reduced in animars rendered thrombocytopaenic (Coyle et al, 1990). It is therefore of interest that two platelet-derived products, platelet factor 4 (PF4) (Chihara et al, 1988) and the related member of the IL-8 supergene family, RANTES (Kameyoshi et al, 1992) have been recently reported to be chemoattractant for eosinophils.…”

“…PAF has been employed in this study to induce airway hyperresponsiveness in rabbits as we have previously reported that this is a useful test system for the evaluation of pharmacological agents and is simpler and more robust method than antigen challenge. We have utilized antigen-immunized rabbits in this study as we have previously shown that PAF can induce airway hyperresponsiveness to inhaled histamine in all neonatally immunized rabbits to some degree (Herd et al, 1992), whereas only in some, but not all normal rabbits (Coyle et al, 1990;Herd et al, 1992). Therefore, in the present study we have investigated the effects of heparin and related compounds on PAF-induced airway hyperresponsiveness and pulmonary cell infiltration in neonatally antigen-immunized rabbits in vivo.…”

The Role of Platelets in Leukocyte Recruitment in Chronic Contact Hypersensitivity Induced by Repeated Elicitation

“…The role of platelets in inflammatory processes is being increasingly recognized, in addition to their function in hemostasis and thrombosis. [1][2][3][4][5][6][7][8] Platelets accumulate in inflammatory sites concomitantly with leukocytes 1,2 and regulate a variety of inflammatory responses by secreting or activating adhesion proteins, growth factors, chemokines, cytokine-like factors, and coagulation factors. These proteins induce widely differing biological activities, including cell adhesion, chemotaxis, cell survival, and proliferation, all of which accelerate the inflammatory process.…”