Role of lung apolipoprotein A-I in idiopathic pulmonary fibrosis: antiinflammatory and antifibrotic effect on experimental lung injury and fibrosis.
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is caused by alterations in expression of proteins involved in multiple pathways, including matrix deposition, inflammation, injury, and repair.


OBJECTIVE
To understand the pathogenic changes in lung protein expression in IPF and to evaluate apolipoprotein (Apo) A-I as a candidate therapeutic molecule.


METHODS
Two-dimensional electrophoresis was adopted for differential display proteomics. Reverse-transcriptase polymerase chain reaction, Western blotting, immunohistochemical staining, and ELISA were performed for identification and quantitative measurement of Apo A-I in bronchoalveolar lavage fluids from subjects with IPF and experimental bleomycin-induced mice.


RESULTS
Sixteen protein spots showed differences in relative intensity between IPF (n = 14) and healthy control subjects (n = 8). Nano liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed increase of haptoglobulin and decrease of alpha(1)-antitrypsin, alpha(1)-antichymotrypsin, macrophage capping protein, angiotensinogen, hemoglobin chain B, Apo A-I, clusterin, protein disulfide isomerase A3, immunoglobulin, and complement C4A in IPF compared with normal control subjects (P = 0.006-0.044). Apo A-I concentrations were lower in bronchoalveolar lavage fluids from subjects with IPF (n = 28) than in normal control subjects (n = 18; P < 0.01). In bleomycin-treated mice, Apo A-I protein in BALF was lower than that in sham-treated control animals. Immunohistochemical analysis showed positive staining on intraalveolar macrophages and epithelial cells of the lungs. Intranasal treatment with Apo A-I protein reduced the bleomycin-induced increases in number of inflammatory cells and collagen deposition in sham-treated mice in a dose-dependent manner.


CONCLUSIONS
Alterations of several inflammatory and antiinflammatory proteins in the lungs may be related to the pathogenesis of IPF, and local treatment with Apo A-I is very effective against the development of experimental lung injury and fibrosis.
Kim
Tae Hoon
TH
Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University, Bucheon Hospital, 1174 Jung-Dong, Wonmi-Ku, Bucheon, Kyeonggi-Do, South Korea.
Lee
Yoo Hoon
YH
Kim
Kyung Hun
KH
Lee
Shin Hwa
SH
Cha
Ji Yeon
JY
Shin
Eun Kyoung
EK
Jung
Seok
S
Jang
An Soo
AS
Park
Sung Woo
SW
Uh
Soo Taek
ST
Kim
Young Hoon
YH
Park
Jai Soung
JS
Sin
Hwa Gyoun
HG
Youm
Wook
W
Koh
Eun Suk
ES
Cho
Sun Young
SY
Paik
Young Ki
YK
Rhim
Tai Youn
TY
Park
Choon Sik
CS
D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D001761:Bleomycin; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D040901:Proteomics / Q000379:methods; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016632:Apolipoprotein A-I; D012333:RNA, Messenger; D001761:Bleomycin