Role of Lung Apolipoprotein A-I in Idiopathic Pulmonary Fibrosis: Antiinflammatory and Antifibrotic Effect on Experimental Lung Injury and Fibrosis

Am J Respir Crit Care Med. 2010 Sep 1;182(5):633-42. doi: 10.1164/rccm.200905-0659OC. Epub 2010 May 12.

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is caused by alterations in expression of proteins involved in multiple pathways, including matrix deposition, inflammation, injury, and repair.

Objectives: 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.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apolipoprotein A-I / biosynthesis*
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism
  • Apolipoprotein A-I / therapeutic use*
  • Bleomycin
  • Blotting, Western
  • Bronchoalveolar Lavage Fluid / chemistry
  • Disease Models, Animal
  • Electrophoresis, Gel, Two-Dimensional
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Foam Cells / metabolism
  • Foam Cells / pathology
  • Humans
  • Idiopathic Pulmonary Fibrosis / drug therapy*
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Idiopathic Pulmonary Fibrosis / physiopathology
  • Lung / metabolism
  • Lung / pathology
  • Lung / physiopathology
  • Male
  • Mice
  • Middle Aged
  • Proteomics / methods
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / drug therapy
  • Pulmonary Fibrosis / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Apolipoprotein A-I
  • RNA, Messenger
  • Bleomycin