Matrix Metalloproteinase-9 Deficiency Results in Enhanced Allergen-Induced Airway Inflammation

Abstract

Matrix metalloproteinases (MMPs) are a large family of endopeptidases that proteolytically degrade extracellular matrix. Many different cells produce MMP-9, and levels have been shown to be up-regulated in patients with allergic asthma. The aim of this study was to investigate the in vivo role of MMP-9 during allergen-induced airway inflammation. Acute allergic pulmonary eosinophilia was established in MMP-9 knockout (KO) and wild-type (WT) control mice by sensitization and challenge with OVA. Cell recruitment was significantly increased in both bronchoalveolar lavage (BAL) and lung tissue compartments in MMP-9 KO mice compared with WT mice. This heightened cell recruitment was primarily due to increased eosinophils and Th2 cells in the BAL and lung tissue of MMP-9 KO mice in comparison with WT controls. Moreover, levels of the Th2 cytokines, IL-4 and IL-13, and the chemokines eotaxin/CCL11 and macrophage-derived chemokine/CCL22 were substantially increased in MMP-9 KO mice compared with WT after OVA challenge. Resolution of eosinophilia was similar between MMP-9 KO and WT mice, but Th2 cells persisted in BAL and lungs of MMP-9 KO mice for longer than in WT mice. Our results indicate that MMP-9 is critically involved in the recruitment of eosinophils and Th2 cells to the lung following allergen challenge, and suggest that MMP-9 plays a role in the development of Th2 responses to allergen.

Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis

“…Even in the standard allergic asthma model of Mmp9 knockout mice, totally discrepant results have been reported. 4,5 It is therefore possible that subtle differences in environmental or genetic backgrounds are responsible for the changes in MMP9 expression/activity. Dissection of the mechanistic link between MMP9 variations and predisposition to sensitization or disease risk is very difficult at present.…”

“…1 Matrix metalloproteinases (MMPs) are a family of enzymes that not only degrade the extracellular matrix but also mediate activation of other proteases and secretion of cytokines, thereby affecting inflammatory processes. 2,3 MMP9, also known as gelatinase B, was shown to be an important mediator of inflammation in a murine model of asthma 4,5 and in immune complex-mediated lung injury. 6 In a mouse asthma model, loss of the MMP9 gene was found to inhibit the development of allergic inflammation by impairing the recruitment of dendritic cells (DCs) into the alveoli and the local production of proallergic chemokines by DCs.…”

Matrix metalloproteinases and the regulation of tissue remodelling

“…The same MMP can have different roles in different conditions. For example, MMP9 contributes to inflammation in mouse models of stroke, heart attack, Alzheimer's disease, some aspects of asthma and other lung inflammatory conditions, aortic aneurysms and autoimmune encephalomyelitis 9,106-110 ; however, it functions as an anti-inflammatory agent in models of inflammatory skin and kidney diseases 89,111,112 . Current data indicate that MMP12 contributes to emphysema 113,114 , whereas MMP3 and MMP9 contribute to skin inflammatory conditions 89,115 .…”

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

“…Levels of IL-1␤, IL-4, and macrophage inflammatory protein-2 (MIP-2) were measured in lung homogenates and BAL fluid using standard ELISA kits purchased from R&D and BD Biosciences. These mediators were chosen as representative Th1 and Th2 cytokines and a chemokine that have shown differences in other studies dealing with inflammation and MMP-9 knockout mice (32,33,28). Limits of detection were 15 pg/ml (IL-1␤ and MIP-2) and 31 pg/ml (IL-4).…”