COL4A3 degradation may depend on MMP9 in experimental asthma exacerbations

COL4A3, an extracellular matrix (ECM) component, is highly degraded in severe type 2 exacerbating asthma and associated with increased chymase positive mast cells in an asthmatic mouse model. However, inhibiting mast cell chymase was insufficient to rescue COL4A3 from degradation in the exacerbating murine model. Plasminogen urokinase activator receptor (PLAUR) has previously been reported to be required for matrix-metallo-proteinase 9 (MMP9) activation, which is essential to COL4A3 degradation. Here, we investigated whether an alternative pathway involving MMP9 and PLAUR may contribute to an increased COL4A3 degradation in asthma exacerbations.

C57BL/6n mice were sensitized to OVA (Ovalbumin, Sigma, Germany) by 3 intraperitoneal injections on days 1, 14 and 21. Mice were exposed 3 times to an OVA (OVA grade V, Sigma) aerosol (1% wt/vol in PBS) on days 26, 27 and 28 to induce acute allergic airway inflammation and Polyinosinic-cytidylic acid (Poly I:C) challenge was introduced on day 28 via aerosol. 50μg Fulacimstat, a chymase inhibitor (MCE, Germany) was administered intra-tracheally on days 25, 26, 27 and 28 via an aerosol. Chymase activity (Sigma, Germany), MMP9 concentration (Mesoscale discovery, USA) were measured in mice lung homogenate.

COL4A3 degradation was found to be increased in OVA model and remained significantly elevated in the exacerbation group (OVA+Poly I:C) after Fulacimstat treatment (p<0.01). Whole lung homogenate chymase activity increased significantly in OVA and OVA+Poly I:C groups (vs controls, p<0.05), whilst Fulacimstat treatment had no significant difference in OVA and OVA+Poly I:C groups. MMP9 concentration was significantly increased in the OVA+Poly I:C group as compared to any other group (p<0.05).

Our data suggests that there was no elevated chymase activity during exacerbation after Fulacimstat treatment. MMP9 along with PLAUR was upregulated during exacerbation. Further research is needed to confirm this potential alternative mechanism leading to the degradation of COL4A3 in severe type 2 exacerbating asthma.

Conflict of Interest

No

Publication History

Article published online:
21 September 2022