Microsatellite DNA instability and COPD exacerbations

Abstract

Increased frequency of microsatellite DNA instability (MSI) has been detected in the sputum of chronic obstructive pulmonary disease (COPD) patients. The aim of the present study was to investigate the relationship between MSI in sputum cells and exacerbation frequency, which is an important parameter in the clinical course of the disease.Induced sputum samples and peripheral blood obtained from 36 patients with COPD at stable state were analysed. The control group consisted of 30 nonsmoking healthy subjects. DNA was extracted and analysed for MSI using the following microsatellite markers: RH70958, D5S207, D6S2223, D6S344, D6S263, G29802, D13S71, D14S588, D14S292 and D17S250. Following MSI analysis, exacerbations were recorded for 3 yrs in total.No MSI was detected in healthy nonsmokers. A total of 18 (50%) out of 36 patients exhibited MSI in their sputum cells. Patients who exhibited MSI showed significantly increased frequency of exacerbations compared with patients that did not. In addition, a significantly increased frequency of purulent and of severe type exacerbations was found in patients exhibiting MSI. Patients positive for marker G29802, D13S71 or D14S588 presented increased exacerbation frequency.The significant association between microsatellite DNA instability and chronic obstructive pulmonary disease exacerbations indicates that somatic mutations could be involved in the pathogenesis and natural history of the disease.

Somatic DNA alterations in lung epithelial barrier cells in COPD patients

“…We have recently detected microsatellite DNA instability (MSI) and/or loss of heterozygosity (LOH) in sputum cells of COPD and asthmatic patients. [5,7,[18][19][20]. To our knowledge MSI and/or LOH have not yet been detected in BAL samples from COPD patients.…”

“…antigen, IL4, beta-adrenergic receptor, tumour necrosis factor, serine proteinase inhibitor genes (serpines), protease inhibitor (PI6, and PI9) endothelin, perforin, α1-antitrypsin, apoptosis-antagonising transcription factor [5,[19][20]. This marker targets a locus in chromosomal region 5q near the coding region for interleukin 4 (IL-4), a pro-inflammatory cytokine that is upregulated and associated with mucous cell hyperplasia and mucus hypersecretion in COPD patients [27,28].…”

“…However the particular sputum and/or BAL cell population exhibiting this genetic instability has not yet been identified. Thus, in continuation of our previous work [5,[18][19][20], the specific aims of this study were to examine whether airway and bronchoalveolar cells are prone to somatic acquired genetic alterations by evaluating sputum and BALF cells and to determine which specific cell population is affected by these somatic acquired genetic alterations. The identification of the susceptible cell population to somatic DNA damage in COPD may elucidate an important component of disease pathogenesis.…”

“…Loss of heterozygosity and microsatellite DNA instability are genetic alterations that have M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 been initially reported in a number of human cancers and in precancerous and malignant lesions of smokers [8][9][10][11][12][13][14][15][16][17]. However, during recent years such phenomena have also been detected in various benign pulmonary and extra-pulmonary diseases [5,7,[18][19][20]. We have recently detected microsatellite DNA instability (MSI) and/or loss of heterozygosity (LOH) in sputum cells of COPD and asthmatic patients.…”

Genomic instability in chronic airway inflammatory diseases

“…These results suggested that somatic mutations could be involved in the pathogenesis of the disease. [31] Mitochondrial DNA damage Mitochondrial DNA (mtDNA) contributes to oxidation resistance, which is an important determinant that affects COPD susceptibility. It was reported that mtDNA is about 30-fold more sensitive to exogenous oxidants than nuclear DNA.…”