IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema - PubMed (original) (raw)
IL-17A modulates oxidant stress-induced airway hyperresponsiveness but not emphysema
Mariona Pinart et al. PLoS One. 2013.
Abstract
IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R) signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R(-/-) and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours) for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm) and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R(-/-), chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R(-/-) mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R(-/-) mice. p38-mitogen-activated protein kinase (MAPK) and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R(-/-) ozone-exposed mice. Lung inflammation scores were not altered in IL-17R(-/-) mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R(-/-) mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
Figure 1. Concentration-response curves to acetylcholine (ACh) and –log provocative concentration of ACh required to increase lung resistance (RL) by 100% from baseline (PC100).
C57/BL6 and IL-17R−/− mice were exposed to air or to ozone. Data is expressed as mean ± S.E.M. **p<0.01; ***p<0.001, compared with to air-exposed mice.
Figure 2. Acetylcholine (ACh)-induced isometric bronchial contractile tension.
Air- and ozone-exposed C57/BL6 mice (6 in air- and 9 in ozone-exposed) and IL17RA−/− mice (6 in air- and 5 in ozone-exposed) were studied. Data expressed as mean ±S.E.M. *p<0.05, **p<0.01, ***p<0.001, compared with air-exposed mice.
Figure 3. Effect of SB239063 (10−6 M) on acetylcholine (ACh)-induced bronchial contractile responses.
Air-exposed C57/BL6 mice (n = 6; Panel A) and IL-17R−/− mice (n = 6; Panel B) and ozone-exposed C57/BL6 mice (n = 9; Panel C) and IL-17R−/− mice (n = 6; Panel D) were studied. Under each condition, the effect of SB239063 has been compared to responses in the absence of this inhibitor. Data presented as mean±SEM. *p<0.05; **p<0.01 compared with SB239063-treated tissues.
Figure 4. Effect of dexamethasone (10−6 M) on acetylcholine (ACh)-induced bronchial contractile responses.
Air-exposed C57/BL6 mice (n = 6; Panel A) and IL-17R−/− mice (n = 6; Panel B) and ozone-exposed C57/BL6 mice (n = 9; Panel C) and IL-17R−/− mice (n = 6; Panel D) were studied. Under each condition, the effect of dexamethasone has been compared to responses in the absence of this inhibitor. Data presented as mean±SEM. *p<0.05 compared with dexamethasone-treated tissues.
Figure 5. Mean linear intercept (Lm) in the lungs of air- and ozone exposed mice (Panel A).
Lungs inflated at 25 cm of water were sectioned and stained with haematoxylin and eosin and microscopically assessed for Lm. Ozone exposed C57/BL6 mice and IL-17R−/− mice showed increased Lm (alveolar enlargement) compared with their appropriate air-exposed control mice. Emphysema score in the lungs of air- and ozone exposed mice (Panel B). Compared with air exposed mice, the emphysema score was increased in ozone-exposed C57/BL6 and IL-17R−/−mice, while it was increased further in ozoneexposed IL-17R−/− mice. Data are expressed as means ± SEM. *p<0.05; **p<0.01; ***p<0.001. Representative histological sections of mouse lungs (Panel C i, ii, iii & iv). Lung sections were stained with haematoxylin and eosin after 6 weeks of exposure to ozone showing enlargement of alveolar spaces in C57/BL6 (Panel C ii) and IL-17A−/− mice (Panel C iv).
Figure 6. Inflammation score in the airways and lungs of air- and ozone-exposed mice.
Compared with air exposed control mice, the inflammation score was increased significantly in ozone exposed C57/BL6 mice but not in IL-17R−/−mice. Data are expressed as means ± SEM. *p<0.01.
Figure 7. Levels of lung IL-17, IL-1β and TNFα.
C57/Bl6 and IL-17R−/− mice were exposed to air or to ozone. Data shown as mean ± SEM for n = 5 in each group; *p<0.05 compared to air in the same species; #p<0.05 compared to C57/Bl6 mice with corresponding exposure.
Figure 8. Lung levels of phosphorylated ERK1/2, p38 MAPK and JNK 1/2/3.
C57/Bl6 and IL-17R−/− mice were exposed to air or to ozone. Data shown as mean ± SEM for n = 5 in each group; *p<0.05 compared to air in the same species; #p<0.05 compared to C57/Bl6 mice with corresponding exposure. RFU: Relative fluorescence unit.
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