Reduced inflammatory response in cigarette smoke exposed Mrp1/Mdr1a/1b deficient mice

Margaretha Van Der Deen,Elisabeth G De Vries,Dirkje S Postma,Huib A Kerstjens,Rik J Scheper,Hetty Timmer-Bosscha,Barry W Van Der Strate,Wim Timens

doi:10.1186/1465-9921-8-49

Abstract

BackgroundTobacco smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD), though the mechanisms of its toxicity are still unclear. The ABC transporters multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp/MDR1) extrude a wide variety of toxic substances across cellular membranes and are highly expressed in bronchial epithelium. Their impaired function may contribute to COPD development by diminished detoxification of noxious compounds in cigarette smoke.MethodsWe examined whether triple knock-out (TKO) mice lacking the genes for Mrp1 and Mdr1a/1b are more susceptible to develop COPD features than their wild-type (WT) littermates. TKO and WT mice (six per group) were exposed to 2 cigarettes twice daily by nose-only exposure or room air for 6 months. Inflammatory infiltrates were analyzed in lung sections, cytokines and chemokines in whole lung homogenates, emphysema by mean linear intercept. Multiple linear regression analysis with an interaction term was used to establish the statistical significances of differences.ResultsTKO mice had lower levels of interleukin (IL)-7, KC (mouse IL-8), IL-12p70, IL-17, TNF-alpha, G-CSF, GM-CSF and MIP-1-alpha than WT mice independent of smoke exposure (P < 0.05). IL-1-alpha, IL-6, IL-8, IL-13, IL-17, TNF-alpha, G-CSF, GM-CSF and MCP-1 increased after smoke exposure in both groups, but the increase in IL-8 was lower in TKO than WT mice (P < 0.05) with a same trend for G-CSF (P < 0.10). Smoke-induced increase in pulmonary inflammatory cells in WT mice was almost absent in TKO mice. The mean linear intercept was not different between groups.ConclusionMrp1/Mdr1a/1b knock-out mice have a reduced inflammatory response to cigarette smoke. In addition, the expression levels of several cytokines and chemokines were also lower in lungs of Mrp1/Mdr1a/1b knock-out mice independent of smoke exposure. Further studies are required to determine whether dysfunction of MRP1 and/or P-gp contribute to the pathogenesis of COPD.

Highlights

Tobacco smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD), though the mechanisms of its toxicity are still unclear
Cytokines and chemokines Levels of IL-7, IL-8, IL-12p70, IL-17, TNFα, granulocyte-colony stimulating factor (G-CSF), GMCSF and MIP1α in whole lung homogenates were significantly lower in triple knock-out (TKO) mice than WT mice independent of smoke exposure (Table 1)
After 6 months smoke exposure, IL-1α, IL-6, IL-8, IL-13, IL-17, TNFα, G-CSF, granulocyte-macrophage-colony stimulating factor (GM-CSF) and MCP-1 in lungs of mice were elevated in TKO and WT mice (Table 1)

Summary

Introduction

Tobacco smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD), though the mechanisms of its toxicity are still unclear. The ABC transporters multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp/MDR1) extrude a wide variety of toxic substances across cellular membranes and are highly expressed in bronchial epithelium. Their impaired function may contribute to COPD development by diminished detoxification of noxious compounds in cigarette smoke. Tobacco smoke generates oxidative stress in the lungs and is the principal risk factor for the development of chronic obstructive pulmonary disease (COPD). Proteins of the ATP-binding cassette (ABC) superfamily such as multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp, encoded by the MDR1 gene) protect against oxidative stress, chemotherapeutic drugs and xenobiotics [1,2] by transporting a wide variety of toxic substances across cellular membranes. A defective function may play a role in the pathogenesis of lung cancer and COPD

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