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Role of Abl in airway hyperresponsiveness and airway remodeling.

Cleary RA, Wang R, Wang T, Tang DD - Respir. Res. (2013)

Bottom Line: Interestingly, conditional knockout of Abl did not affect the levels of IL-13 and CCL2 in bronchoalveolar lavage fluid of animals treated with ovalbumin.However, treatment with imatinib and GNF-5 inhibited the ovalbumin-induced increase in IL-13 and CCL2 as well as airway resistance and smooth muscle growth in animals.These results suggest that the altered expression of Abl in airway smooth muscle may play a critical role in the development of airway hyperresponsiveness and airway remodeling in asthma.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Avenue MC-8, Albany, NY 12208, USA. tangd@mail.amc.edu.

ABSTRACT

Background: Asthma is a chronic disease that is characterized by airway hyperresponsiveness and airway remodeling. The underlying mechanisms that mediate the pathological processes are not fully understood. Abl is a non-receptor protein tyrosine kinase that has a role in the regulation of smooth muscle contraction and smooth muscle cell proliferation in vitro. The role of Abl in airway hyperresponsiveness and airway remodeling in vivo is largely unknown.

Methods: To evaluate the role of Abl in asthma pathology, we assessed the expression of Abl in airway tissues from the ovalbumin sensitized and challenged mouse model, and human asthmatic airway smooth muscle cells. In addition, we generated conditional knockout mice in which Abl expression in smooth muscle was disrupted, and then evaluated the effects of Abl conditional knockout on airway resistance, smooth muscle mass, cell proliferation, IL-13 and CCL2 in the mouse model of asthma. Furthermore, we determined the effects of the Abl pharmacological inhibitors imatinib and GNF-5 on these processes in the animal model of asthma.

Results: The expression of Abl was upregulated in airway tissues of the animal model of asthma and in airway smooth muscle cells of patients with severe asthma. Conditional knockout of Abl attenuated airway resistance, smooth muscle mass and staining of proliferating cell nuclear antigen in the airway of mice sensitized and challenged with ovalbumin. Interestingly, conditional knockout of Abl did not affect the levels of IL-13 and CCL2 in bronchoalveolar lavage fluid of animals treated with ovalbumin. However, treatment with imatinib and GNF-5 inhibited the ovalbumin-induced increase in IL-13 and CCL2 as well as airway resistance and smooth muscle growth in animals.

Conclusions: These results suggest that the altered expression of Abl in airway smooth muscle may play a critical role in the development of airway hyperresponsiveness and airway remodeling in asthma. Our findings support the concept that Abl may be a novel target for the development of new therapy to treat asthma.

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Effects of imatinib and GNF-5 on airway resistance and contractile response of tracheal rings from OVA-sensitized and challenged mice. (A) BALB/c mice were sensitized and challenged with OVA in the presence of imatinib, GNF-5 or vehicle (V). Airway resistance in these mice was then measured. Intranasal instillation of imatinib and GNF-5 inhibited RAW in mice sensitized and challenged by OVA. *Significantly lower airway resistance in animals treated with imatinib or GNF-5 compared to animals treated with vehicle (P < 0.05, n = 7–8). (B) Treatment with imatinib and GNF-5 attenuated the OVA-sensitized tracheal contraction in vitro. Contractile force is normalized to maximal force of rings from OVA- and vehicle-treated mice. *Significantly lower tracheal contraction from animals treated with imatinib or GNF-5 compared to vehicle-treated animals (P < 0.05, n = 7–8).
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Figure 6: Effects of imatinib and GNF-5 on airway resistance and contractile response of tracheal rings from OVA-sensitized and challenged mice. (A) BALB/c mice were sensitized and challenged with OVA in the presence of imatinib, GNF-5 or vehicle (V). Airway resistance in these mice was then measured. Intranasal instillation of imatinib and GNF-5 inhibited RAW in mice sensitized and challenged by OVA. *Significantly lower airway resistance in animals treated with imatinib or GNF-5 compared to animals treated with vehicle (P < 0.05, n = 7–8). (B) Treatment with imatinib and GNF-5 attenuated the OVA-sensitized tracheal contraction in vitro. Contractile force is normalized to maximal force of rings from OVA- and vehicle-treated mice. *Significantly lower tracheal contraction from animals treated with imatinib or GNF-5 compared to vehicle-treated animals (P < 0.05, n = 7–8).

Mentions: We also evaluated the effects of the Abl inhibitors imatinib and GNF-5 on AHR in asthmatic animals. The OVA sensitization and challenge increased airway resistance in BALB/c mice as compared to BALB/c mice treated with PBS (Figure 6A). In contrast, the OVA-induced increase in airway resistance was reduced in the animals treated with imatinib or GNF-5 (Figure 6A). In addition, treatment with imatinib or GNF-5 inhibited the ACh-induced contraction in isolated mouse tracheal rings of OVA-sensitized and challenged mice (Figure 6B).


Role of Abl in airway hyperresponsiveness and airway remodeling.

Cleary RA, Wang R, Wang T, Tang DD - Respir. Res. (2013)

Effects of imatinib and GNF-5 on airway resistance and contractile response of tracheal rings from OVA-sensitized and challenged mice. (A) BALB/c mice were sensitized and challenged with OVA in the presence of imatinib, GNF-5 or vehicle (V). Airway resistance in these mice was then measured. Intranasal instillation of imatinib and GNF-5 inhibited RAW in mice sensitized and challenged by OVA. *Significantly lower airway resistance in animals treated with imatinib or GNF-5 compared to animals treated with vehicle (P < 0.05, n = 7–8). (B) Treatment with imatinib and GNF-5 attenuated the OVA-sensitized tracheal contraction in vitro. Contractile force is normalized to maximal force of rings from OVA- and vehicle-treated mice. *Significantly lower tracheal contraction from animals treated with imatinib or GNF-5 compared to vehicle-treated animals (P < 0.05, n = 7–8).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3852349&req=5

Figure 6: Effects of imatinib and GNF-5 on airway resistance and contractile response of tracheal rings from OVA-sensitized and challenged mice. (A) BALB/c mice were sensitized and challenged with OVA in the presence of imatinib, GNF-5 or vehicle (V). Airway resistance in these mice was then measured. Intranasal instillation of imatinib and GNF-5 inhibited RAW in mice sensitized and challenged by OVA. *Significantly lower airway resistance in animals treated with imatinib or GNF-5 compared to animals treated with vehicle (P < 0.05, n = 7–8). (B) Treatment with imatinib and GNF-5 attenuated the OVA-sensitized tracheal contraction in vitro. Contractile force is normalized to maximal force of rings from OVA- and vehicle-treated mice. *Significantly lower tracheal contraction from animals treated with imatinib or GNF-5 compared to vehicle-treated animals (P < 0.05, n = 7–8).
Mentions: We also evaluated the effects of the Abl inhibitors imatinib and GNF-5 on AHR in asthmatic animals. The OVA sensitization and challenge increased airway resistance in BALB/c mice as compared to BALB/c mice treated with PBS (Figure 6A). In contrast, the OVA-induced increase in airway resistance was reduced in the animals treated with imatinib or GNF-5 (Figure 6A). In addition, treatment with imatinib or GNF-5 inhibited the ACh-induced contraction in isolated mouse tracheal rings of OVA-sensitized and challenged mice (Figure 6B).

Bottom Line: Interestingly, conditional knockout of Abl did not affect the levels of IL-13 and CCL2 in bronchoalveolar lavage fluid of animals treated with ovalbumin.However, treatment with imatinib and GNF-5 inhibited the ovalbumin-induced increase in IL-13 and CCL2 as well as airway resistance and smooth muscle growth in animals.These results suggest that the altered expression of Abl in airway smooth muscle may play a critical role in the development of airway hyperresponsiveness and airway remodeling in asthma.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Cardiovascular Sciences, Albany Medical College, 47 New Scotland Avenue MC-8, Albany, NY 12208, USA. tangd@mail.amc.edu.

ABSTRACT

Background: Asthma is a chronic disease that is characterized by airway hyperresponsiveness and airway remodeling. The underlying mechanisms that mediate the pathological processes are not fully understood. Abl is a non-receptor protein tyrosine kinase that has a role in the regulation of smooth muscle contraction and smooth muscle cell proliferation in vitro. The role of Abl in airway hyperresponsiveness and airway remodeling in vivo is largely unknown.

Methods: To evaluate the role of Abl in asthma pathology, we assessed the expression of Abl in airway tissues from the ovalbumin sensitized and challenged mouse model, and human asthmatic airway smooth muscle cells. In addition, we generated conditional knockout mice in which Abl expression in smooth muscle was disrupted, and then evaluated the effects of Abl conditional knockout on airway resistance, smooth muscle mass, cell proliferation, IL-13 and CCL2 in the mouse model of asthma. Furthermore, we determined the effects of the Abl pharmacological inhibitors imatinib and GNF-5 on these processes in the animal model of asthma.

Results: The expression of Abl was upregulated in airway tissues of the animal model of asthma and in airway smooth muscle cells of patients with severe asthma. Conditional knockout of Abl attenuated airway resistance, smooth muscle mass and staining of proliferating cell nuclear antigen in the airway of mice sensitized and challenged with ovalbumin. Interestingly, conditional knockout of Abl did not affect the levels of IL-13 and CCL2 in bronchoalveolar lavage fluid of animals treated with ovalbumin. However, treatment with imatinib and GNF-5 inhibited the ovalbumin-induced increase in IL-13 and CCL2 as well as airway resistance and smooth muscle growth in animals.

Conclusions: These results suggest that the altered expression of Abl in airway smooth muscle may play a critical role in the development of airway hyperresponsiveness and airway remodeling in asthma. Our findings support the concept that Abl may be a novel target for the development of new therapy to treat asthma.

Show MeSH
Related in: MedlinePlus