Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis.
OBJECTIVE
Aberrant angiogenesis and defective epithelial repair are key features of idiopathic pulmonary fibrosis (IPF). Endostatin is an antiangiogenic peptide with known effects on endothelial cells. This study aimed to establish the levels of endostatin in the bronchoalveolar lavage fluid (BALF) in IPF and to investigate its actions on distal lung epithelial cells (DLEC) and primary type II cells.


METHODS
20 patients with IPF and 10 controls underwent BAL. Endostatin was measured by ELISA. BALF cytokines and matrix metalloproteinase (MMP)-3 were measured by Luminex array. Primary DLEC monolayers were wounded and treated with endostatin. Apoptosis and cell viability were assessed.


RESULTS
Endostatin was elevated in the BALF and plasma of patients with IPF compared with normal controls. There was a negative correlation between endostatin, forced vital capacity and gas transfer. Endostatin correlated with a number of proinflammatory cytokines and MMP3. Physiological endostatin doses inhibited DLEC wound repair by 44% in an effect that was partially FasL and caspase dependent. Endostatin increased apoptosis rates by 8% and reduced their viability by 34%. Similar effects of endostatin were seen in primary type II cells in terms of inhibition of wound repair and proliferation.


CONCLUSIONS
Elevated BALF endostatin levels correlated with a number of elevated cytokines, MMP3 and lung function in IPF. Endostatin is a novel inhibitor of DLEC wound repair, inducing apoptosis and reducing cell viability in a FasL and caspase dependent manner. Endostatin may play a role in aberrant epithelial repair in IPF.
Lung Injury and Fibrosis Treatment Programme, Department of Medical Sciences, Medical School, University of Birmingham, Birmingham, UK.
A G
AG
Richter
S
S
McKeown
S
S
Rathinam
L
L
Harper
P
P
Rajesh
D F
DF
McAuley
R
R
Heljasvaara
D R
DR
Thickett
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D043169:Endostatins / Q000378:metabolism* / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells; D004848:Epithelium; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000737:chemistry; D014797:Vital Capacity; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
D020533:Angiogenesis Inhibitors; D016207:Cytokines; D043169:Endostatins; D019278:Matrix Metalloproteinase 3