Identification of lipocalin and apolipoprotein A1 as biomarkers of chronic obstructive pulmonary disease.
BACKGROUND
Much effort is being made to discover noninvasive biomarkers of chronic airway disease that might enable better management, predict prognosis, and provide new therapeutic targets.


OBJECTIVE
To undertake a comprehensive, unbiased proteomic analysis of induced sputum and identify novel noninvasive biomarkers for chronic obstructive pulmonary disease (COPD).


METHODS
Induced sputum was obtained from patients with COPD with a spectrum of disease severity and from control subjects. Two-dimensional gel electrophoresis and mass spectrometric identification of differentially expressed proteins were first applied to induced sputum from patients with GOLD stage 2 COPD and healthy smoker control subjects. Initial results thus obtained were validated by a combination of immunoassays (Western blotting and ELISA) applied to a large subject cohort. The biomarkers were localized to bronchial mucosa by immunohistochemistry.


RESULTS
Of 1,325 individual protein spots identified, 37 were quantitatively and 3 qualitatively different between the two groups (P < 0.05%). Forty protein spots were subjected to tandem mass spectrometry, which identified 15 separate protein species. Seven of these were further quantified in induced sputum from 97 individuals. Using this sequential approach, two of these potential biomarkers (apolipoprotein A1 and lipocalin-1) were found to be significantly reduced in patients with COPD when compared with healthy smokers. Their levels correlated with FEV(1)/FVC, indicating their relationship to disease severity.


CONCLUSIONS
A potential role for apolipoprotein A1 and lipocalin-1 in innate defense has been postulated previously; our discovery of their reduction in COPD indicates a deficient innate defense system in airway disease that could explain increased susceptibility to infectious exacerbations.
Nicholas
Benjamin L
BL
Inflammatory Cell Biology Group, Division of Infection, Inflammation, and Immunity, Sir Henry Wellcome Laboratories, South Block, Southampton General Hospital, Southampton, UK. bln1@soton.ac.uk
Skipp
Paul
P
Barton
Sheila
S
Singh
Dave
D
Bagmane
Dinesh
D
Mould
Richard
R
Angco
Gilbert
G
Ward
Jon
J
Guha-Niyogi
Binita
B
Wilson
Susan
S
Howarth
Peter
P
Davies
Donna E
DE
Rennard
Stephen
S
O'Connor
C David
CD
Djukanovic
Ratko
R
D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000032:analysis / Q000378:metabolism*; D001249:Asthma / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D015153:Blotting, Western; D029481:Bronchitis, Chronic / Q000378:metabolism; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005540:Forced Expiratory Flow Rates; D006801:Humans; D054834:Lipocalins / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000737:chemistry; D012720:Severity of Illness Index; D012907:Smoking / Q000378:metabolism; D013183:Sputum / Q000737:chemistry / Q000378:metabolism
D016632:Apolipoprotein A-I; D015415:Biomarkers; D054834:Lipocalins