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Am. J. Respir. Crit. Care Med., Volume 165, Number 2, January 2002, 200-205

Airway Hyperresponsiveness in Transgenic Mice Overexpressing Platelet Activating Factor Receptor Is Mediated by an Atropine-Sensitive Pathway

TAKAHIDE NAGASE, SATOSHI ISHII, HIDEO SHINDOU, YASUYOSHI OUCHI, and TAKAO SHIMIZU

Departments of Geriatric Medicine and Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Platelet activating factor (PAF) is a potent mediator potentially involved in the pathogenesis of inflammatory disorders, including bronchial asthma. Recently, transgenic mice overexpressing the PAF receptor (PAFR) gene have been established, and exhibit bronchial hyperresponsiveness, one of the cardinal features of asthma. To elucidate the molecular and pathophysiologic mechanisms underlying PAF-associated bronchial hyperreactivity, we studied airway responsiveness to methacholine (MCh) and serotonin (5-hydroxytryptamine; 5-HT) in PAFR-transgenic mice. In addition, we examined the role of the muscarinic receptor in PAF-induced responses and the binding activities of the muscarinic receptor. The PAFR-transgenic mice exhibited hyperresponsiveness to MCh and PAF; however, no significant differences in 5-HT responsiveness were observed between the control and PAFR-transgenic mice. The administration of atropine significantly blocked PAF-induced responses in PAFR-transgenic mice. There were no differences between the two phenotypes in the binding activities of muscarinic receptor. Morphometric analyses demonstrated that PAFR overexpression did not affect airway structure. These findings suggest that the muscarinic pathway may have a key role in airway hyperresponsiveness associated with PAFR gene overexpression. More generally, PAFR-transgenic mice may provide appropriate models for study of the molecular mechanisms underlying PAF-associated diseases.

    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Keywords: platelet activating factor; asthma; airway hyperresponsiveness; transgenic mouse

Platelet activating factor (PAF) is a proinflammatory phospholipid mediator that has various potent properties (1). PAF mediates its biologic effects via activation of a G-protein- coupled, seven transmembrane receptor (1, 3). Complementary DNAs (cDNAs) and genes for the PAF receptor (PAFR) have been cloned from various species, including guinea pigs and humans (5). To examine the pathophysiologic role of PAF in vivo, we have established transgenic mice ubiquitously overexpressing PAF receptor (12). Recently, we also established a mutant mouse lacking PAFR, and demonstrated that PAF could be involved in anaphylactic responses (13).

It has been indicated that PAF plays a substantial role in the pathogenesis of bronchial asthma (14, 15). Moreover, it has been demonstrated that the level of expression of PAFR messenger RNA (mRNA) in the lung is increased in humans with asthma (16). In asthmatic children, deficiency of plasma PAF acetylhydrolase is associated with respiratory dysfunction (17, 18), and in a mouse model of asthma, recombinant PAF acetylhydrolase inhibits airway inflammation and hyperreactivity (19). Bronchial hyperreactivity, which is a major characteristic of asthma, is augmented by the administration of exogenous PAF (20). However, the exact pathophysiologic roles of PAF in the pathogenesis of bronchial asthma remain to be elucidated.

In the current study, we investigated the pathophysiologic mechanisms underlying PAF-associated airway hyperresponsiveness (AHR). We studied the airway responsiveness of PAFR-transgenic mice to methacholine (MCh) and serotonin (5-hydroxytryptamine; 5-HT). We then examined the involvement of the muscarinic pathway in PAF-induced responses, and performed binding assays for muscarinic receptor. We further assessed airway structure, including smooth muscle, using morphometry.

    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Mice

PAFR-transgenic mice were established as previously described (12). Mutant mice and their littermate controls were used in this study.

Animal Preparation

Animals were anesthetized with pentobarbital sodium (25 mg/kg, intraperitoneally) and ketamine hydrochloride (25 mg/kg, intraperitoneally) in combination, and were mechanically ventilated with tidal volumes of 10 ml/kg, respiratory frequencies of 2.5 Hz and a positive end-expiratory pressure of 2 cm H2O. The thorax was widely opened by means of a midline sternotomy, but the vagus nerve was not sectioned. Lung resistance (RL) and elastance (EL) were measured as previously described (21).

Airway Responsiveness to 5-HT or MCh

Following baseline measurement, each dose of 5-HT aerosol (0.15 to 10 mg/ml) or MCh aerosol (0.63 to 80 mg/ml) was administered for 1 min in a dose-response manner. As previously reported (22, 23), airway responsiveness to 5-HT or MCh was assessed from the concentration of agonists required to increase RL to 200% of baseline values (EC200 RL).

Airway Responsiveness to PAF

Following baseline measurement, each dose of PAF (5 to 20 µg/kg) was administered intravenously and measurements were made.

Effects of Atropine on PAF-Induced Responses

Two minutes before receiving the intravenous bolus of 10 µg/kg PAF, mice were intraperitoneally pretreated with either saline or 10 µmol/kg atropine sulfate. After baseline measurements, PAF was administered via the jugular vein and measurements were made.

Binding Assays for Muscarinic Receptor

From each mouse preparation, five or six whole lungs were obtained and homogenized together in a ×10 volume of binding buffer (25 mM 4-(2-hydroxyethyl)-1-piperazine-N'-2-ethanesulfonic acid [pH 7.4], 0.25 M sucrose, 10 mM MgCl2) containing a proteinase inhibitor cocktail (Complete; Roche, Mannheim, Germany) and 20 µM amidino phenyl methyl sulfonyl fluoride (Sigma, St. Louis, MO). After centrifugation (800 × g for 20 min at 4° C), the supernatants were further centrifuged at 123,000 × g for 1 h. The pellets were mashed once and recentrifuged at 140,000 × g for 1 h. The final pellets were resuspended in the same buffer. The binding assays were done in duplicate in the absence or presence of 50 nM PAF. The reaction mixture consisted of 150 µl of the binding buffer containing [N-methyl-3H]scopolamine (2.51 TBq/ mmol), a nonselective muscarinic antagonist, at increasing concentrations of 0.0625 to 2 nM, and 50 µl of the membrane protein (95 µg). The mixtures were incubated in a 96-well microplate at 25° C for 1.5 h, followed by filtration and washing as described previously (24). The radioactivities of dried filters were determined as reported (24). Nonspecific binding was defined as the binding measured in the presence of 20 µM methacholine.

Binding Assays for PAFR

The lung membrane was obtained as described previously. Binding assays for PAFR were performed in the same manner as previously described, with [3H]-WEB2086, a PAFR-selective antagonist, at increasing concentrations at 3.13 to 100 nM (703 GBq/mmol). Nonspecific binding was defined as the binding in the presence of 50 µM cold WEB2086.

Morphometric Study

In four animals from each group, we quantitated airway smooth muscle and lamina propria, using morphometric techniques as previously reported (25, 26).

Data Analysis

Comparisons of physiologic and morphometric data among the experimental groups were done through analysis of variance (Scheffe's test) or Student's t test. Data are expressed as mean ± SE. Values of p < 0.05 were taken as significant.

    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Airway Responsiveness to 5-HT or MCh Administration

The control and PAFR-transgenic mice showed no significant differences in baseline EL and RL. Figure 1 shows 5-HT dose- response curves for EL in the two groups. There was no difference in elastic responses to 5-HT. MCh dose-response curves for EL are shown in Figure 2. Responses in the PAFR-transgenic mice were significantly greater than in the control group at MCh doses of > 2.5 mg/ml.


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  		Figure 1.   Serotonin (5-HT) dose-response curves for EL in control and PAFR-transgenic mice (n = 4 for each group). BAS = baseline; SAL = saline. Control; Transgenic.


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  		Figure 2.   MCh dose-response curves for EL in control and PAFR-transgenic mice (n = 7 for each group). *p < 0.01 compared with control mice. BAS = baseline; SAL = saline. Control; Transgenic.

Responses for RL are summarized in Figure 3. As shown, there were no differences between the two groups in 5-HT responsiveness. However, airway responsiveness to MCh in PAFR-transgenic mice was significantly greater than in control mice (logEC200 RL = 0.950 ± 0.076 versus 1.462 ± 0.039, p < 0.001).


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  		Figure 3.   Airway responsiveness expressed as the concentration of agonists required to double lung resistance (EC200 RL). *p < 0.001 compared with control mice. 5-HT = serotonin; MCh = methacholine.

Airway Responsiveness to PAF

Following the administration of 20 µg/kg PAF to five PAFR-transgenic mice, two animals died immediately from cardiac arrest, whereas no animals died in the other groups. Responses for EL and RL are shown in Figure 4. After administration of each dose of PAF (5 to 20 µg/kg), significant differences in pulmonary responses were observed between the control and PAFR-transgenic mice, and the effects of PAF were enhanced at higher doses in the PAFR-transgenic group.


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  		Figure 4.   PAF-induced responses in EL (A) and RL (B) in control and PAFR-transgenic mice (n = 3 or 4 for each group). *p < 0.001 compared with control mice.

Effects of Atropine on PAF-Induced Pulmonary Responses

Effects of atropine on PAF-induced pulmonary responses are demonstrated in Figure 5. As shown, the control mice exhibited no responses to 10 µg/kg PAF after either saline or atropine pretreatment. In the PAFR-transgenic mice pretreated with saline, PAF administration induced increases in RL and EL. Pretreatment with atropine significantly inhibited PAF-induced responses in the PAFR-transgenic mice.


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  		Figure 5.   Effects of atropine on PAF-induced responses in EL (A) and RL (B) (n = 4 for each group). *p < 0.001 compared with other groups.

Binding Assays for Muscarinic Receptor and PAFR

Results of binding assays for muscarinic receptor are summarized in Table 1. In either the absence or presence of PAF, there were no differences between the control and PAFR-transgenic mice in dissociation constant (Kd) or binding maximum (Bmax) values for [N-methyl-3H]scopolamine, a nonselective muscarinic antagonist, suggesting that the binding activities for muscarinic receptors in the PAFR-transgenic lungs were similar to those in the controls.

                              
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TABLE 1

 RESULTS OF BINDING ASSAYS FOR MUSCARINIC RECEPTOR

As shown in Figure 6, the binding activities for PAFR in the PAFR-transgenic lungs were markedly greater than in the control lungs.


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  		Figure 6.   Binding assays for PAFR in control and PAFR-transgenic mouse lung membranes, showing isoforms for binding of [3H]- labelled WEB2086 to membrane fractions. Because of low specific binding to control membranes, Scatchard analysis was not performed. Results shown are means from duplicate wells. Two independent membrane fractions (Lots #1 and #2), from whole lungs for each genotype, were used.

Morphometric Study

Table 2 summarizes the morphometric data for airway size and roundness. There were no significant differences between the PAFR and control mice in number of airways, airway size, or airway roundness, indicating that there were no significant biases between the experimental groups in terms of airway selection.

                              
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TABLE 2

 MORPHOMETRIC DATA FOR AIRWAYS

As shown in Figure 7, there were no significant differences between the PAFR and control groups in thickness of the lamina propria or airway smooth muscle. In addition, no significant difference in inner wall area was observed between the control and PAFR-transgenic mice (0.224 ± 0.018 and 0.215 ± 0.015, respectively), suggesting that the airway structure of PAFR-transgenic mice is not altered as compared with that of control mice.


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  		Figure 7.   Thickness of lamina propria and airway smooth muscle in control and PAFR-transgenic mice. Area/Abm* = area normalized with ideally relaxed airway size.

    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The results of the experiments reported here show that airway responsiveness to MCh and PAF in PAFR-transgenic mice was significantly greater than in control mice. Blockade of the muscarinic pathway with atropine inhibited PAF-induced responses in the PAFR-transgenic mice, whereas the overexpression of PAFR did not change the binding activity of muscarinic receptor. Similarly, airway responsiveness to 5-HT was unaffected by overexpression of the PAFR gene, and morphometric analyses showed that airway structure, including airway smooth muscle, was not altered by overexpression of the PAFR gene. These findings suggest that the muscarinic pathway may have a key role in AHR associated with overexpression of the PAFR gene. Thus, expression of the PAFR gene is involved in airway responsiveness to MCh in mice through a functional but not a structural mechanism.

Before the results of the study are discussed, the issue of anesthesia warrants consideration. In the study, it was necessary to reduce the vagal function of the animals used, since effects of the experimental procedures on vagal activity might have affected the results and interpretation of data. We therefore chose to use anesthesia with pentobarbital sodium and ketamine hydrochloride in combination with one another. It has been demonstrated that both pentobarbiturate and ketamine have inhibitory effects on vagal pathways (27). Although the vagus nerve was not surgically sectioned, we believe that vagal function was significantly attenuated with the anesthesia applied in this study and that comparisons between the control and PAFR-transgenic mice are meaningful.

The airway responsiveness to MCh of the PAFR-transgenic mice was markedly greater than that of control mice, suggesting that the transgenic mice have an asthmalike phenotype. There was also a marked difference in MCh-induced changes in lung elasticity between the asthmalike and normal phenotypes (Figure 2). It has been reported that changes in EL reflect lung parenchymal alterations and stiffening of the lungs induced by various contractile stimuli (30), although the contraction of conducting airways can also cause changes in EL (31). By comparison, increases in RL represent decreases in airway luminal cross-sectional area (30). In the present study, enhanced responses in both EL and RL to MCh administration were observed in the PAFR-transgenic mice, suggesting that overexpression of the PAFR gene elicits increased responses to MCh in both the lung parenchyma and airways.

It has been postulated that PAF may be related to AHR in various species, including human (14, 15). The administration of exogenous PAF increases airway responsiveness in humans (20), whereas a specific PAFR antagonist (Y-24180) reduces AHR to MCh in asthmatic patients (32). In their recent study, Henderson and colleagues (19) found that increasing plasma levels of PAF acetylhydrolase through its administration was effective in blocking late-phase pulmonary inflammation in a murine model of asthma. However, the exact mechanism for the involvement of PAF in AHR remains to be clarified. In the current study, the molecular and pathophysiologic mechanisms underlying AHR were examined with PAFR-transgenic mice overexpressing the PAFR gene.

One possible mechanism for the involvement of PAF in AHR is that PAF and PAFR gene expression affect airway structure, and especially the lamina propria and airway smooth muscle. Airway remodeling, including thickening of airway smooth muscle, is a feature in asthmatic subjects and could be involved in bronchial hyperresponsiveness (33, 34). Lambert and Paré have shown that a marked increase in airway responsiveness is theoretically induced by thickening of the airway wall, including its smooth muscle layer (33). In the current study, however, no significant difference in thickness of either the lamina propria or airway smooth muscle was observed in the control as opposed to the PAFR-transgenic mice. These results suggest that overexpression of the PAFR gene has little effect on airway remodeling in mice. Whereas PAF may have proliferative effects on various cells (35), it seems that in the mouse model used in our study, the effect of PAF on airway smooth muscle proliferation is not remarkable. In this model, AHR elicited by overexpression of the PAFR gene may be associated with airway dysfunction, but not with airway remodeling.

It has been shown that in PAFR-transgenic mice, a high level of transgenic mRNA exists in the trachea (12), and one could assume from this that airway smooth-muscle cells overexpressing PAFR may play a role in PAF-induced bronchopulmonary responses. Consistently, the binding activities for PAFR in the PAFR-transgenic mouse lungs in our study were remarkably augmented in comparison with those of the controls. After each dose of PAF given in vivo, marked pulmonary responses were observed in the PAFR-transgenic mice as compared with the controls. Notably, the effects of PAF were more remarkable at the higher doses in the PAFR-transgenic mice, indicating that PAF per se has a significant role in the AHR of PAFR-transgenic mice to PAF. On the other hand, blockade of the muscarinic pathway completely ablated PAF-induced responses in the PAFR-transgenic mice. This indicates that PAF-induced bronchoconstriction is mediated by an atropine-sensitive pathway. Stimler-Gerard (36) has postulated that PAF may stimulate neural elements proximal to the end plate to release constrictive neurotransmitters including acetylcholine, which might explain the mechanism for the findings in our study.

The results of the binding assays indicate that PAFR overexpression per se has little effect on the binding activity of muscarinic receptors in either the absence or presence of PAF. The interaction between PAF and muscarinic receptors may therefore instead occur through an indirect pathway. It has been reported that PAF may affect the biologic actions of other potent mediators, such as thromboxanes and leukotrienes, which are involved in AHR (37). Potentially, overexpression of the PAFR gene may modulate the production levels of these potent mediators.

Airway responsiveness to 5-HT was not affected by overexpression of the PAFR gene. This observation suggests that PAF and the PAFR gene may be specifically related to bronchial responsiveness to MCh, but not to 5-HT. Recently, it was demonstrated that AHR induced by 5-HT and acetylcholine is inherited independently in mice, and that murine nonspecific AHR is determined by multiple genes (38). The results of the present study indicate that mutation of the PAFR gene affects muscarinic receptor-specific responsiveness, but not general bronchial responsiveness.

Genetic features are potentially associated with the etiology of asthma. On the basis of the inheritance pattern of bronchial asthma a number of genes could have substantial roles in its pathogenesis (39). Murine models of asthma have recently been used to investigate individual genes associated with AHR (40). Since PAF may be one of the potent mediators involved in bronchial asthma (14, 15, 20), genes regulating the function and metabolism of PAF could be targets of study in the pathogenesis of asthma. These genes consist of the PAFR gene (11, 41) and genes encoding PAF-metabolic enzymes, including PAF acetylhydrolases (42, 43). The PAFR-transgenic mice used in the present study may contribute to study of the genetic roles of PAF in bronchial asthma.

PAF has pleiotropic and pathophysiologic effects on various cells and organs (1). It exerts its actions at concentrations as low as 10-12 M in some cells, and almost always at levels of at least 10-9 M as an intercellular messenger (2). PAF activates phospholipase A2 (PLA2), protein kinase C, protein tyrosine phosphorylation, and gene expression (1, 2, 44). It has been shown that PAFR knockout mice exhibit markedly reduced anaphylactic responses as compared with wild-type mice, suggesting that PAF plays an important role in the development of anaphylactic shock (13). On the other hand, PAFR-transgenic mice show an increased lethality to bacterial lipopolysaccharide endotoxin (12). Melanogenesis and melanocytic proliferation were observed in the skin of PAFR-transgenic mice, and melanoma was occasionally seen in aged PAFR-transgenic mice (12). Recent studies done with genetically-engineered mice have shown that cytosolic PLA2 (cPLA2) is essential in the production of PAF (24, 45), indicating that both cPLA2 and PAF are key mediators in the development of inflammatory disorders. For example, both cPLA2 and PAF play significant roles in the molecular mechanism underlying acute lung injury (46). The PAFR-transgenic mice used in our study may further provide novel insights for study of the pathophysiologic roles of PAF and PAFR in vivo.

In summary, the PAFR-transgenic mice in our study exhibited hyperresponsiveness to MCh and PAF, but not to 5-HT. The muscarinic pathway may have a key role in PAF-induced responses in these PAFR-transgenic mice. Meanwhile, binding activities for muscarinic receptor were not altered by the overexpression of PAFR. We observed no differences in airway structure between the control and PAFR-transgenic mice to suggest that PAFR gene overexpression would be involved in MCh airway responsiveness by acting as a functional mediator. The PAFR-transgenic mice may provide appropriate models for studying molecular and pathophysiologic mechanisms underlying diseases related to PAF metabolism.

    Footnotes

Correspondence and requests for reprints should be addressed to Dr. T. Nagase, Department of Geriatric Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113-8655. E-mail: takahide-tky{at}umin.ac.jp

(Received in original form June 27, 2001 and accepted in revised form November 5, 2001).

Acknowledgments: The authors thank Y. Suzuki, K. Ishihara, and M. Ito (of the University of Tokyo) for their technical assistance.

Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan.

    References
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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