Role of mitogen-activated protein kinase phosphatase-1 in corticosteroid insensitivity of chronic oxidant lung injury

Farhana Hussain,Sima Shirali,Andrew R Clark,Kian Fan Chung,Mariona Pinart,Alaina J Ammit,Jie Zhu,Feng Li

doi:10.1016/j.ejphar.2014.10.003

Farhana Hussain, Sima Shirali + Show 6 more

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https://doi.org/10.1016/j.ejphar.2014.10.003

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Abstract

Oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and in the induction of corticosteroid (CS) insensitivity. Chronic ozone exposure leads to a model of COPD with lung inflammation and emphysema. Mitogen-activated protein kinase phosphatase-1 (MKP-1) may underlie CS insensitivity in COPD. We determined the role played by MKP-1 by studying the effect of corticosteroids in wild-type C57/BL6J and MKP-1−/− mice after chronic ozone exposure. Mice were exposed to ozone (3ppm, 3h) 12 times over 6 weeks. Dexamethasone (0.1 or 2mg/kg; intraperitoneally) was administered before each exposure. Mice were studied 24h after final exposure. In ozone-exposed C57/BL6J mice, bronchial hyperresponsiveness (BHR) was not inhibited by both doses of dexamethasone, but in MKP-1−/− mice, there was a small inhibition by high dose dexamethasone (2mg/kg). There was an increase in mean linear intercept after chronic ozone exposure in both strains which was CS-insensitive. There was lesser inflammation after low dose of dexamethasone in MKP-1−/− mice compared to C57/Bl6J mice. Epithelial and collagen areas were modulated in ozone-exposed MKP-1−/− mice treated with dexamethasone compared to C57/Bl6J mice. MKP-1 regulated the expression of MMP-12, IL-13 and KC induced by ozone but did not alter dexamethasone׳s effects. Bronchial hyperresponsiveness, lung inflammation and emphySEMa after chronic exposure are CS-insensitive, and the contribution of MKP-1 to CS sensitivity in this model was negligible.

Highlights

(Nrf2) knockout mice, which, through their diminished capacity to mount antioxidant defences, develop increased susceptibility to emphysema and lung inflammation following cigarette smoke exposure (Rangasamy et al, 2004)
There was an increase in bronchial hyperresponsiveness (BHR) in all groups of mice compared to control in both strains (Fig. 1A and B)
In MKP-1À/À mice, there was still a significant reduction in PC100 after ozone exposure after 0.1 mg/kg dexamethasone but not after the 2 mg/kg dose indicating a potential reversal of ozone induced BHR

Summary

Introduction

(Nrf2) knockout mice, which, through their diminished capacity to mount antioxidant defences, develop increased susceptibility to emphysema and lung inflammation following cigarette smoke exposure (Rangasamy et al, 2004). Direct exposure of mice to an oxidant gas, ozone, results in emphysema and chronic lung inflammation reminiscent of COPD (Triantaphyllopoulos et al, 2011). Oxidant stress causes bronchial hyperresponsiveness resulting from an increase in contractility of the airways (Li et al, 2011). In order to investigate whether MKP-1 can modulate the effects of oxidative stress and their responses to CS, we used a model of chronic exposure to ozone that leads to alveolar space enlargement and destruction together with a chronic inflammatory process (6). We examined the effect of CS in a chronic ozone model, and determined the role played by MKP-1 by studying the MKP-1À/À mouse

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