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Secreted Frizzled-Related Protein-1 Potentiates the Inflammatory Response of Allergic Asthma
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A5807 - Secreted Frizzled-Related Protein-1 Potentiates the Inflammatory Response of Allergic Asthma
Author Block: E. Arteaga-Solis1, J. M. D'Armiento2, J. Sonett3; 1Pediatrics, Columbia University Medical Center, New York, NY, United States, 2Dept of Medicine, Columbia Univ, New York, NY, United States, 3Columbia University, New York, NY, United States.
Rationale Asthma is caused by heterogeneous pathological processes that affect the airways. It affects roughly 25 million Americans underscoring the need to better understand the processes that lead to airway narrowing and remodeling. Wnt signaling has been associated with asthma and shown to play a role in the repair and remodeling processes in lung disease. We tested whether Secreted Frizzled-Related Protien-1 (SFRP-1), a direct inhibitor of Wnt signaling, played a role in allergic asthma and whether modulating its activity could affect the disease.
Methods Human THP1 were differentiated into TH1 (M1) or TH2 (M2) macrophages with LPS and INF-γ treatment or IL13 and IL4 treatment, respectively. QPCR analyses was utilized to confirm THP1 differentiation and assess gene expression profile. Female 9-week old wild type (WT) mice were treated with intranasal house dust mite (WTHDM) or vehicle. The mice were also treated with Sfrp-1 and WAY316606, a direct inhibitor of Sfrp-1. Lung mechanics were assessed with a Flexivent. Broncho-alveolar lavage and histomorphometric analyses were utilized to assess airway inflammation and remodel. Sfrp-1 null mice (Sfrp-1-/-) were also utilized and analyzed as above.
Results QPCR analysis demonstrated a five-fold increase in expression of SFRP-1 in M2; whereas, there was no change in SFRP-1 expression in M1 macrophages. In WTHDM mouse lungs, there was a two-fold increase in Sfrp-1 expression compared to control. Treatment of WTHDM mice with WAY normalized their airway resistance (Rn) at baseline and response to methacholine, i.e. airway hyper responsiveness, compared to vehicle-treated WTHDM. Bronchoalveolar lavage analyses revealed that the WAY treated WTHDM also exhibited decreased airway inflammation compared to vehicle treated mice. On the other hand, Sfrp-1 treatment of WTHDM significantly increased Rn at baseline was not sufficient to change their response to methacholine or airway inflammation compared to vehicle-treated WTHDM mice. Consistent with the pharmacological studies, Sfrp-1-/- mice have decreased Rn at baseline and response to methacholine compared to WT littermate controls.
Conclusions These studies demonstrate a significant role for Sfrp-1 in allergic asthma regulating airway inflammation and lung function. The findings identify a potentially novel therapeutic agent in allergic asthma.
Author Block: E. Arteaga-Solis1, J. M. D'Armiento2, J. Sonett3; 1Pediatrics, Columbia University Medical Center, New York, NY, United States, 2Dept of Medicine, Columbia Univ, New York, NY, United States, 3Columbia University, New York, NY, United States.
Rationale Asthma is caused by heterogeneous pathological processes that affect the airways. It affects roughly 25 million Americans underscoring the need to better understand the processes that lead to airway narrowing and remodeling. Wnt signaling has been associated with asthma and shown to play a role in the repair and remodeling processes in lung disease. We tested whether Secreted Frizzled-Related Protien-1 (SFRP-1), a direct inhibitor of Wnt signaling, played a role in allergic asthma and whether modulating its activity could affect the disease.
Methods Human THP1 were differentiated into TH1 (M1) or TH2 (M2) macrophages with LPS and INF-γ treatment or IL13 and IL4 treatment, respectively. QPCR analyses was utilized to confirm THP1 differentiation and assess gene expression profile. Female 9-week old wild type (WT) mice were treated with intranasal house dust mite (WTHDM) or vehicle. The mice were also treated with Sfrp-1 and WAY316606, a direct inhibitor of Sfrp-1. Lung mechanics were assessed with a Flexivent. Broncho-alveolar lavage and histomorphometric analyses were utilized to assess airway inflammation and remodel. Sfrp-1 null mice (Sfrp-1-/-) were also utilized and analyzed as above.
Results QPCR analysis demonstrated a five-fold increase in expression of SFRP-1 in M2; whereas, there was no change in SFRP-1 expression in M1 macrophages. In WTHDM mouse lungs, there was a two-fold increase in Sfrp-1 expression compared to control. Treatment of WTHDM mice with WAY normalized their airway resistance (Rn) at baseline and response to methacholine, i.e. airway hyper responsiveness, compared to vehicle-treated WTHDM. Bronchoalveolar lavage analyses revealed that the WAY treated WTHDM also exhibited decreased airway inflammation compared to vehicle treated mice. On the other hand, Sfrp-1 treatment of WTHDM significantly increased Rn at baseline was not sufficient to change their response to methacholine or airway inflammation compared to vehicle-treated WTHDM mice. Consistent with the pharmacological studies, Sfrp-1-/- mice have decreased Rn at baseline and response to methacholine compared to WT littermate controls.
Conclusions These studies demonstrate a significant role for Sfrp-1 in allergic asthma regulating airway inflammation and lung function. The findings identify a potentially novel therapeutic agent in allergic asthma.
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