Blocking of EDA‐Fibronectin Attenuates Airway Hyperresponsivenss in a Murine Model of Acute and Chronic Allergen‐Induced Airway Remodeling

Rationale Airway remodeling refers to changes in the structural components of the airway wall such as subepithelial fibrosis, increased myofibroblasts and increased airway smooth muscle. Airway hyperresponsiveness (AHR) is a defining feature of asthma and may be attributable to the presence of airway remodeling. Fibronectin is a 440‐kd dimeric major ECM glycoprotein that plays a regulatory role during embryogenesis, wound healing and maintenance of tissue integrity. EDA‐FN is a splice variant of fibronectin. Increased levels of EDA‐FN were reported in the lungs of asthmatic patients and of allergen exposed mice. We have previously shown that EDA −/− mice exposed to chronic allergen challenge have attenuated airway fibrosis and AHR. Aim To determine whether blocking the EDA‐FN in‐vivo in wild type mice (genetically “intact”) attenuates the development of airway remodeling and airway hyperresponsiveness in a murine model of acute and chronic allergen‐induced “asthma”. Methods BALB/c female mice (6 groups, 5–10/group) were exposed to saline (Sal) or ovalbumin (OVA) (intraperitoneal sensitization followed by inhalations on alternate days for 1 or 4 weeks). Three of the groups received intraperitoneal EDA‐FN blocking antibody (every 5 days) beginning prior to sensitization. AHR in response to methacholine (Flexivent), bronchoalveolar lavage (BAL) cell counts and histological evaluation (H&E, Masson Trichrome) was performed 24h after the last inhalation followed by collagen content and cytokine expression in the lung tissue. Results OVA treated mice showed a significant increase in AHR (airway resistance) in both the acute (relative to baseline: 4.12±0.48) and chronic (3.93±0.36) groups in comparison with saline treated mice (2±0.1) and this increase was abolished by EDA‐FN blocking antibody in acute OVA treated mice (2.76±0.24, p<0.03), but not in the chronic model (OVA 3.93±0.36 vs OVA+Ab EDA‐FN 4.06±0.35). OVA exposed mice had marked BAL eosinophilia (acute: 77.5±2.8% and chronic 57.5±2.8%) that was significantly lowered by anti EDA‐FN treatment (58.8±3% acute and 39.3±3.2% chronic, p<0.001 for both acute and chronic) while antibody treatment alone was similar to saline. Histologic evaluation also showed less peribronchial inflammation in the acute model in response to blocking antibody but no reduction in the chronic model. The increase in lung collagen content seen in response to chronic OVA‐exposure was completely abolished in the presence of anti EDA‐FN antibody (93.4±4.6 mg collagen/50 mg tissue vs. 56.3±2.9 mg collagen/50 mg tissue, p<0.001 compared to SAL 66±7.6 mg collagen/50 mg tissue). Conclusions In a murine model of allergen induced “asthma”, inhibition of EDA‐FN attenuates airway hyperresponsiveness, airway fibrosis and airway inflammation, however these effects vary, depending on chronicity of allergen and antibody exposure. Support or Funding Information Israel Science Foundation