Abstract
ATP-binding cassette (ABC) transporters are a family of transmembrane proteins that can transport a wide variety of substrates across biological membranes in an energy-dependent manner. Many ABC transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) are highly expressed in bronchial epithelium. This review aims to give new insights in the possible functions of ABC molecules in the lung in view of their expression in different cell types. Furthermore, their role in protection against noxious compounds, e.g. air pollutants and cigarette smoke components, will be discussed as well as the (mal)function in normal and pathological lung. Several pulmonary drugs are substrates for ABC transporters and therefore, the delivery of these drugs to the site of action may be highly dependent on the presence and activity of many ABC transporters in several cell types. Three ABC transporters are known to play an important role in lung functioning. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can cause cystic fibrosis, and mutations in ABCA1 and ABCA3 are responsible for respectively Tangier disease and fatal surfactant deficiency. The role of altered function of ABC transporters in highly prevalent pulmonary diseases such as asthma or chronic obstructive pulmonary disease (COPD) have hardly been investigated so far. We especially focused on polymorphisms, knock-out mice models and in vitro results of pulmonary research. Insight in the function of ABC transporters in the lung may open new ways to facilitate treatment of lung diseases.
Highlights
The prime role of the airways is to conduct air into and out of the lung and to form a first line of defence against undesired constituents of inhaled air
Our preliminary results indicate that multidrug resistance-associated protein 1 (MRP1) expression is diminished in bronchial epithelium of chronic obstructive pulmonary disease (COPD) patients and that lower expression is related to worse lung function [10]
Little is known about the function of ATP-binding cassette (ABC) transporters that are expressed in the lung their overall expression is very high compared to many other organs [6]
Summary
The prime role of the airways (trachea, bronchi, bronchioles and terminal bronchioles) is to conduct air into and out of the lung and to form a first line of defence against undesired constituents of inhaled air. LTB4 levels are elevated in sputum and exhaled breath condensate of COPD patients [72,73] This is thought to result from a higher amount of neutrophils present, yet lower functional MRP1 expression may play a role, according to the observations in Mrp (-/-) mice [10,71]. CFTR is the only member of the ABC superfamily which is not an active transporter It functions as a chloride channel and in normal human airway tissue CFTR is highly expressed at the luminal side in serous cells of the submucosal glands. In wild-type and mutant CFTR expressing Sf9 insect cells, it was demonstrated that besides chloride transport, another function of CFTR is transport of GSH in a nucleotide-dependent manner [141] This observation suggests that CFTR plays a role in the control of oxidative stress. It was suggested that ABCA3 plays a role in phospholipid metabolism, since it closely resembles ABCA1 and ABCA4 that are known to transport phospholipids
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