Changes in pulmonary surfactant function and composition in bleomycin-induced pneumonitis and fibrosis.
Bleomycin is a widely accepted cancer drug but may induce life-threatening interstitial lung disease in a subset of patients. We evaluated the effect of bleomycin administration on pulmonary surfactant function and composition in rabbit lungs. In order to obtain a uniform response to bleomycin, aerosol technology was employed for bronchoalveolar delivery of 1.8 U/kg b.w. bleomycin. On days 4, 8, 16, 24, 32, and 64 after challenge, bronchoalveolar lavages were performed. Sham-aerosolized rabbits served as controls. In the early acute respiratory distress syndrome (ARDS)-like post-bleomycin period (4-16 days), marked loss of surface activity of the large surfactant aggregate (LA) fraction of surfactant was noted. In parallel, reduced percentages of LA, but only minor changes in surfactant apoproteins (SP)-A, SP-B, and SP-C, were encountered. Analysis of the surfactant lipid profile showed impressively enhanced cholesterol and significantly decreased phosphatidylglycerol (PG) levels. The relative content of dipalmitoyl-PC (DPPC) was slightly increased, and a several-fold increase within the 1-O-alkyl-2-acyl subclass of PC was observed. During the prolonged fibroproliferative period, a highly significant downregulation of SP-B and SP-C levels was observed. This was paralleled by an upregulation of the total extracellular phospholipid pool, with a far-reaching normalization of the (phospho)-lipid profile. The biophysical surfactant function never fully normalized within the 64-day observation period. In conclusion, bleomycin caused marked abnormalities of pulmonary surfactant, with the profile of changes being different between the early ARDS and the late fibrotic phase.
Schmidt
Reinhold
R
Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany. reinhold.schmidt@innerer.med.uni-giessen.de
Ruppert
Clemens
C
Markart
Philipp
P
Lübke
Norbert
N
Ermert
Leander
L
Weissmann
Norbert
N
Breithecker
Andreas
A
Ermert
Monika
M
Seeger
Werner
W
Günther
Andreas
A
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001059:Apoproteins / Q000378:metabolism; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D005260:Female; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011663:Pulmonary Surfactants / Q000378:metabolism*; D011817:Rabbits; D015898:Tomography Scanners, X-Ray Computed
D000336:Aerosols; D000903:Antibiotics, Antineoplastic; D001059:Apoproteins; D010743:Phospholipids; D011663:Pulmonary Surfactants; D001761:Bleomycin; C025703:bleomycetin