Laboratory markers for COPD in “susceptible” smokers

Abstract

Smoking is the major risk factor for the development of chronic obstructive pulmonary disease. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition. However, only a relatively small proportion of smokers–about 15%–will develop clinically relevant COPD.

Allergy, airway hyper-responsiveness (AHR) to methacholine, and gender differences have been proposed to identify individuals susceptible to the development of COPD. However, variable response to cigarette smoke clearly suggests genetic susceptibility. Among the COPD candidate genes are those (a) that effect the production of proteases and antiproteases, (b) modulate the metabolism of toxic substances in cigarette smoke, (c) are involved with mucocilliary clearance, and (d) that influence inflammatory mediators. Recently, sputum cells from smokers with and without COPD were tested for Microsatellite DNA Instability (MSI) with positive results. This finding suggests that MSI can be a useful marker of genetic susceptibility and thereby indicate destabilization of the genome in the “susceptible” smoker.

Nevertheless, COPD lacks established viable biomarkers to predict and monitor disease progression and outcome variables. Such monitoring tools may be induced sputum, exhaled air condensate, peripheral blood, urine, bronchial biopsies, and bronchoalveolar lavage fluid (BALF). This review summarizes recent research on potential laboratory markers in smokers and subsequent COPD development.

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a treatable and preventable disease state characterized by airflow limitation, but not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory lung response to noxious particles and gases, primarily caused by cigarette smoking. Although COPD substantially affects the lung, it also produces significant systemic consequences [1].

Smoking is considered the major risk factor for development of COPD and accounts for 89–90% of the cumulative risk in the USA [2]. However, not all smokers will develop COPD. In fact, only a small proportion (about 15%) will develop clinical relevant disease [3], [4]. Why only a fraction of smokers develop clinical manifestations of the disease has been a focus of research in COPD pathogenesis.

The impact of COPD in women reveals substantial gender differences in susceptibility, severity and response to management of COPD [5]. Occupational exposures to various dusts and toxins, air pollution, especially fine particulate indoor pollution from biomass fuels, disproportionately affects women by early-onset and non-smoking related COPD [5], [6].

Despite these findings, COPD lacks established screening markers and viable biomarkers to monitor disease progression and outcome. Many inflammatory cells, mediators and enzymes are involved in the disease process, but their relative importance is still poorly understood. Noninvasive monitoring tools may be the induced sputum, exhaled air condensate, peripheral blood, urine, and bronchoalveolar lavage fluid (BALF). In selective cases, however, bronchial biopsies could be performed to monitor the disease process.

Among the candidate genes that have been studied in COPD are ones regulating proteases and antiproteases, genes that modulate the metabolism of toxic substances in cigatette smoke, genes involved in mucocilliary clearance, and genes that influence inflammatory mediators [7] (Fig. 1). Recently, detection of Microsatellite DNA Instability (MSI) has suggested that this test can be considered as a useful genetic screening marker for the “susceptible” smoker [8], [9], [10].