title: Secretory leukoprotease inhibitor attenuates lung injury induced by continuous air embolization into sheep.
abstract: Continuous air embolization (CAE) into the pulmonary arterial circulation of sheep results in functional and structural changes of chronic pulmonary hypertension. Release of elastin peptides into lung lymph during CAE and attenuation of CAE-induced pulmonary hypertension by neutrophil depletion suggest that neutrophil elastase may contribute to these changes. To investigate this notion, we treated awake sheep with a potent neutrophil elastase inhibitor, recombinant secretory leukoprotease inhibitor (SLPI) (100 mg/day by aerosol), during 12 days of CAE (CAE+SLPI; n = 7). Controls included sheep receiving CAE + vehicle (VEH) (n = 6), VEH alone (n = 3), and SLPI alone (n = 3). SLPI significantly attenuated the CAE-induced increases in lung lymph flow (day 8; 2.3 +/- 0.5 vs. 5.6 +/- 1.7 ml/15 min), protein clearance (day 8; 1.36 +/- 0.32 vs. 3.08 +/- 0.84 ml/15 min), and elastin peptide concentration (day 8; 243 +/- 41 vs. 398 +/- 44 ng/ml). SLPI delayed the onset of sustained pulmonary hypertension from day 8 to day 12. Both CAE groups showed similar structural changes in the pulmonary arteries. SLPI was well tolerated in control sheep and did not affect hemodynamics or structure. We conclude that serine proteases may contribute to the early initiation of chronic pulmonary hypertension but do not play a striking role in its eventual development.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Gossage
authors.forename: E A
authors.initials: EA
authors.lastname: Perkett
authors.forename: J M
authors.initials: JM
authors.lastname: Davidson
authors.forename: B C
authors.initials: BC
authors.lastname: Starcher
authors.forename: D
authors.initials: D
authors.lastname: Carmichael
authors.forename: K L
authors.initials: KL
authors.lastname: Brigham
authors.forename: B
authors.initials: B
authors.lastname: Meyrick
mesh_terms: D000336:Aerosols; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D004549:Elastin / Q000097:blood / Q000378:metabolism; D004618:Embolism, Air / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury; D008196:Lymph / Q000187:drug effects / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000502:physiology; D011659:Pulmonary Gas Exchange / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000336:Aerosols; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; D004549:Elastin