A murine model of toluene diisocyanate–induced asthma can be treated with matrix metalloproteinase inhibitor

Abstract

Background: Toluene diisocyanate (TDI) is a leading cause of occupational asthma. TDI-induced asthma is an inflammatory disease of the airways that is associated with airway remodeling. However, there are little data available on the role of matrix metalloproteinases (MMPs) in TDI-induced asthma. Objective: We evaluated whether MMP-9 participates in the airway inflammation in TDI-induced asthma. An additional aim of the present study was to determine whether MMP inhibitors could be effective therapeutic agents for TDIinduced asthma. Methods: We developed a murine model of TDI-induced asthma to examine the involvement of MMPs by performing 2 sensitizations with 3% TDI and 1 challenge with 1% TDI using ultrasonic nebulization. Toluene diisocyanate (TDI), a low-molecular-weight compound widely used in the production of polyurethane foams, automobile paints, varnishes, and related products, is a leading cause of occupational asthma. 1,2 TDIinduced asthma is characterized by hyperresponsiveness and inflammation of the airways. 2,3 This inflammation is associated with infiltration of lymphocytes, eosinophils, and neutrophils into the bronchial lumen. 3,4 Airway remodeling, which often occurs in the bronchial tree, probably arises as a consequence of inflammatory processes.The extracellular matrix is a dynamic structure, and its homeostasis depends on an equilibrium between synthesis and degradation of extracellular matrix components. A balance between the expression of proteases and antiproteases, particularly the matrix metalloproteinases (MMPs) and their inhibitors, maintains this homeostasis under normal conditions. The expression of these same proteases and antiproteases is critical in tissue repair and remodeling in some pulmonary inflammatory diseases. [5][6][7][8] In allergic asthma, the mechanisms of remodeling of the bronchial tree caused by extracellular matrix deposition are well characterized. Of the MMP family, MMP-9 is the major proteinase that induces bronchial remodeling in asthma. 9,10 In addition, MMP-9 induces the migration of eosinophils and neutrophils across basement membranes. 11,12 Recently, MMPs were reported to play a crucial role in the infiltration of ovalbumin-induced airway inflammatory cells and the induction of airway hyperresponsiveness in a murine model of asthma. 13 However, there are little data available on the role of MMPs in TDIinduced asthma.In the present study we developed a murine model of TDI-induced asthma to examine the involvement of

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

“…A wealth of data implicates proteinases such as MMPs in asthma and chronic obstructive pulmonary disease (COPD), but comparatively little is known about the source of these enzymes and precisely how they contribute to allergic airway inflammation (24)(25)(26)(27)(28)(29)(33)(34)(35)(36). Their presence in the airway during allergen challenge suggests an important role in the acute inflammatory response, while their capacity to cleave preferred peptide sequences renders them an attractive imaging target and putative functional biomarkers for disease.…”

“…MMPs have received heightened attention because they are elevated in experimental models of allergic airway inflammation (24)(25)(26)(27)(28)(29)36) and in the airways of asthmatics (25,(33)(34)(35)(36). They also degrade tissue extracellular matrix; promote the recruitment, proliferation, and survival of inflammatory cells; and participate directly in bronchoconstriction and airway remodeling (25,37,38).…”

“…Pulmonary eosinophils and other cells, such as macrophages, mast cells, and smooth muscle cells, produce MMPs - such as MMP-2, -3, -9, -12, -13, and -14 - as well as cathepsins B, S, L, H, and K, which are thought to contribute to the pathogenesis of asthma (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). MMPs have received heightened attention because they are elevated in experimental models of allergic airway inflammation (24)(25)(26)(27)(28)(29)36) and in the airways of asthmatics (25,(33)(34)(35)(36).…”

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

“…Although administration of GM6001 did not alter the ovalbumin (OVA)-induced asthma phenotype in mice, there was a dose-dependent inhibition of inflammatory cell egression with concomitant accumulation of inflammatory cells in the lung parenchyma [21]. Similarly, in a murine model of toluene diisocyanate-induced occupational asthma (TDI-OA), the broad-spectrum MMP inhibitors MMPI-I and MMPI-II decreased the number of inflammatory cells in BAL fluids [58,59].…”

Immunological determinants in a murine model of toluene diisocyanate-induced asthma

“…Herrick and colleagues [20] have published a murine model of HDI asthma where BALB/c mice were epicutaneously sensitized with HDI followed by intranasal respiratory challenge with HDI-albumin, resulting in BALF eosinophilia and marked lung inflammation composed of lymphocytes and eosinophils. In the murine model of TDI asthma applied by Lee et al, the intranasal sensitization with TDI followed by the respiratory challenge with ultrasonically nebulized TDI resulted in airway hyperresponsiveness, inflammatory infiltrates around bronchioles, a predominantly neutrophilic response in the BALF [21,22]. In our experiment, we also investigated the role of inflammatory mediators in TDI-induced asthma.…”