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. 1999 Mar;126(5):1191-9.
doi: 10.1038/sj.bjp.0702394.

Characterization of airway and vascular responses in murine lungs

H D Held  1 , C Martin, S Uhlig
Affiliations

Characterization of airway and vascular responses in murine lungs

H D Held et al. Br J Pharmacol. 1999 Mar.

Abstract

1. We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision-cut lung slices. 2. Airways: The EC50 (microM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP-receptor agonist), 0.1/0.06>endothelin-1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml(-1), respectively. Adenosine (< or =1 mM), bombesin (< or =100 microM), histamine (< or =10 mM), LTC4 (< or =1 microM), PAF (0.25 microM) and substance P (< or =100 microM) had only weak effects (<5% of Mch) on RL. 3. Vessels: The EC50 (microM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.05<endothelin-1, 0.02. The maximum increase in pulmonary artery pressure (PAP) was 11, 41 and 48 cmH2O, respectively. At 250 nM, the activity of PAF was comparable to that of LTC4. At 100 microM only, substance P caused a largely variable increase in PAP. Serotonin, adenosine, bombesin, histamine and Mch had no or only very small effects on PAP. 4. Hyperresponsiveness: In both the IPL and slices, U46619 in subthreshold concentrations (10 nM) reduced the EC50 to 0.6 microM. In the IPL, U46619 raised the maximum airway response to Mch 5 fold and the maximum PAF-induced vasoconstriction 4 fold. 5.

Conclusion: Murine precision-cut lung slices maintain important characteristics of the whole organ. The maximum reagibility of murine airways to endogenous mediators is serotonin<Mch<U46619<ET-1. The reagibility of the murine pulmonary vasculature is serotonin<LTC4 approximately = to PAF<U46619<ET-1. The airway and vessel hyperreactivity induced by U46619 raises the possibility that thromboxane contributes directly to airway hyperresponsiveness in various experimental and clinical settings.

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Figures

Figure 1
Figure 1
Airway resistance (left column) and mean pulmonary artery pressure (PAP, right column) in response to repetitive perfusion with methacholine (A and B), the thromboxane receptor agonist U46619 (C and D), serotonin (E and F), leukotriene C4 (G and H) or endothelin-1 (I and J). Methacholine (Mch, 10 μM), U46619 (0.1 μM), serotonin (5-HT, 1 μM) or leukotriene C4 (LTC4, 10 nM) were perfused for the time indicated by the black horizontal bars, i.e. 20 min or 30 min for ET-1. The airway resistance and the mean pulmonary artery pressure are expressed in relative terms as the change induced by the agonist.
Figure 2
Figure 2
Cumulative concentration response curves of changes in airway resistance in lungs perfused with methacholine (A) or serotonin (B). Methacholine (Mch) and serotonin (5-HT) were perfused for 20 min at each concentration. The airway resistance is expressed in relative terms as the change induced by the agonists.
Figure 3
Figure 3
Concentration dependent increase in airway resistance and mean pulmonary artery pressure (PAP) by U46619 (A and B) and ET-1 (C and D). Since both mediators induced hyperresponsiveness when given repetitively to the same lung, each concentration was tested in a separate lung. The time courses of airway resistance (A and C) and mean pulmonary artery pressure (B and D) in response to different concentrations of U46619 and ET-1 (n=3 at each concentration) are shown in this figure. Data are given as means±s.e.mean.
Figure 4
Figure 4
Airway (A) and vascular (B) responses of murine lungs to various mediators. Cumulative concentration-response experiments were carried out for methacholine (n=5) and serotonin (n=3). In these experiments, lungs were perfused for 20 min with each concentration, with intermission periods of 15 min, in which lungs were perfused with buffer only. For U46619 (n=3 for each concentration), leukotriene C4 (n=3 for each concentration) and endothelin-1 (n=3 for each concentration), each concentration was perfused for 30 min in separate lungs. Concentration-response curves were calculated from the area under the curve (AUC), i.e. the time integral of changes in airway resistance (A) or pulmonary artery pressure (B) within 20 min. For platelet activating factor (PAF, n=3) only one concentration, i.e. 250 nM, was tested. Data are given as means±s.e.mean.
Figure 5
Figure 5
Concentration-response curves of murine airways to various mediators in precision-cut lung slices. Precision-cut lung slices were placed under a microscope and incubated with varying concentrations of methacholine, serotonin, U46619, ET-1 or methacholine/1 nM U46619. For methacholine and serotonin cumulative concentration-response curves were performed; for U46619 and ET-1 for each concentration a new slice was used. A single airway was focused and the size of this airway was followed over time. The AUC of the airway size over time was plotted against the agonist concentration. Data are means±s.d. from 3–6 single slices.
Figure 6
Figure 6
U46619-induced AHR to methacholine. A bolus of 10 nmol methacholine was given 15 min before (Mch1) and 15 min after (Mch2) perfusion with different concentrations of U46619 for 30 min (n=3 for each concentration). The change in airway resistance in response to Mch was recorded. The data are expressed as the ratio Mch1/Mch2, i.e. a ratio of 1 means that the responses before and after U46619 were similar. Data are given as means±s.e.mean.
Figure 7
Figure 7
U46619-induced AHR to methacholine. Cumulative concentrations of methacholine were perfused in the absence (n=5) or presence (n=4) of 10 nM U46619. Data are given as mean (AUC of the airway resistance)±s.e.mean.
Figure 8
Figure 8
U46619-induced vascular hyperresponsiveness to PAF. 250 nM PAF were perfused in the absence (n=3) or presence (n=3) of 10 nM U46619. Data are given as the mean of the pulmonary artery pressure±s.e.mean.
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References

    1. ARIMURA A., ASANUMA F., YAGI H., KUROSAWA A., HARADA M. Involvement of thromboxane A2 in bronchial hyperresponsiveness but not lung inflammation induced by bacterial lipopolysaccharide. Eur. J. Pharmacol. 1993;231:13–21. - PubMed
    1. BRUSSELLE G., KIPS J., JOOS G., BLUETHMANN H., PAUWELS R. Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am. J. Respir. Cell Mol. Biol. 1995;12:254–259. - PubMed
    1. DEVILLIER P., BESSARD G. Thromboxane A2 and related prostaglandins in airways. Fundam. Clin. Pharmacol. 1997;11:2–18. - PubMed
    1. GARSSEN J., NIJKAMP F.P., VAN VUGT E., VAN DER VLIET H., VAN LOVEREN H. T cell-derived antigen binding molecules play a role in the induction of airway hperresponsiveness. Am. J. Respir. Crit. Care Med. 1994;150:1528–1538. - PubMed
    1. GARSSEN J., VAN LOVEREN H., VAN DER VLIET H., NIJKAMP F.P. An isometric method to study respiratory smooth muscle responses in mice. J. Pharm. Meth. 1990;24:209–217. - PubMed

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