Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation - PubMed (original) (raw)

Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation

Didier D Cataldo et al. Am J Pathol. 2002 Aug.

Abstract

We investigated the specific role of matrix metalloproteinase (MMP)-9 in allergic asthma using a murine model of allergen-induced airway inflammation and airway hyperresponsiveness in MMP-9(-/-) mice and their corresponding wild-type (WT) littermates. After a single intraperitoneal sensitization to ovalbumin, the mice were exposed daily either to ovalbumin (1%) or phosphate-buffered saline aerosols from days 14 to 21. Significantly less peribronchial mononuclear cell infiltration of the airways and less lymphocytes in the bronchoalveolar lavage fluid were detected in challenged MMP-9(-/-) as compared to WT mice. In contrast, comparable numbers of bronchoalveolar lavage fluid eosinophils were observed in both genotypes. After allergen exposure, the WT mice developed a significant airway hyperresponsiveness to carbachol whereas the MMP-9(-/-) mice failed to do so. Allergen exposure induced an increase of MMP-9-related gelatinolytic activity in WT lung extracts. Quantitative reverse transcriptase-polymerase chain reaction showed increased mRNA levels of MMP-12, MMP-14, and urokinase-type plasminogen activator after allergen exposure in the lung extracts of WT mice but not in MMP-9-deficient mice. In contrast, the expression of tissue inhibitor of metalloproteinases-1 was enhanced after allergen exposure in both groups. We conclude that MMP-9 plays a key role in the development of airway inflammation after allergen exposure.

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Figures

Figure 1.

Figure 1.

Allergen-induced pulmonary inflammation. Photomicrographs depicting the pulmonary tissue of the four groups of mice. WT mice exposed to PBS (a) or OVA (b) and MMP-9−/− mice exposed to PBS (c) or OVA (d). H&E: original magnifications, ×200.

Figure 2.

Figure 2.

Quantification of histological inflammation. Mean peribronchial inflammation scores (a) and cellular composition of the infiltrates (b) were determined in the four groups as described in the Materials and Methods.

Figure 3.

Figure 3.

Zymographic analysis of lung proteins extracts. In WT mice, gelatinolytic activity related to MMP-9 protein was significantly increased after allergen exposure. Both pro-MMP-9 (with a molecular weight of 105 kd) and active MMP-9 (arrow) were detected.

Figure 4.

Figure 4.

Measurements of airway responsiveness to carbachol. Dose response curves of respiratory system resistance expressed as percent increase from baseline against the intravenous carbachol dose in MMP-9+/+ (WT) and MMP-9−/− mice exposed either to PBS or allergens. In this model, airway resistance is calculated from the differential pressure between the pleural cavity and the airways tidal volume and flow. WT mice exposed to OVA (n = 16) are significantly hyperresponsive compared to WT mice exposed to PBS aerosol (n = 9). In contrast MMP-9−/− mice fail to develop allergen-induced AHR.

Figure 5.

Figure 5.

mRNA expression measured by RT-PCR of MMPs, TIMPs, uPA, and PAI. The RNA was extracted from the whole lungs crushed in liquid nitrogen. The results are expressed as a ratio between the intensity of the endogenous band and the band of a synthetic standard RNA and normalized by the same ratio calculated for 28S rRNA. Results are expressed as a number of mRNA copies. a: Representative example of migration on polyacrylamide gels representing TIMP-1 mRNA expression. b–e: The bar graphs represent the ratio 28S rRNA/mRNA and are expressed as mean ± SEM for the gene expression of TIMP-1, MMP-14, MMP-12, and uPA, respectively.

Figure 6.

Figure 6.

IL-13 measurements in the BAL. BAL samples were assessed for IL-13 levels using a commercial enzyme-linked immunosorbent assay. The results are expressed as mean ± SEM.

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