Effects of an intratracheally delivered anti-inflammatory protein (rhCC10) on physiological and lung structural indices in a juvenile model of acute lung injury.
BACKGROUND
Mechanical ventilation results in acute lung trauma that can stimulate processes that alter lung development. Activation of matrix metalloproteinases (MMPs) and their tissue-produced inhibitors (TIMPs) is initiated by the inflammatory response to mechanical ventilation and are involved in breakdown of the basement membrane and parenchymal modeling.


OBJECTIVE
The aim of this study was to test the hypothesis that rhCC10, a lung anti-inflammatory mediator, would foster improved lung function, structural preservation, and a reduction in net MMP activity in a juvenile model of acute lung injury.


METHODS
Twenty-four juvenile rabbits were saline-lavage-injured and treated with 100 or 25 mg/kg surfactant (Survanta, Ross Labs) with or without rhCC10 (Claragen, Inc.; n=6 per group). Animals were ventilated for 4 h, then euthanized for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, MMP-7, and MMP-9 and TIMPs 1 and 2 in the lung.


RESULTS
Apical lung expansion, reduced with the lower dose of surfactant, was partially restored with the addition of rhCC10. Alveolar septal wall thickness was reduced (p<0.05) with low-dose surfactant plus rhCC10 compared to high-dose surfactant alone. Increased within-group variance in MMP-2 and MMP-9 proteolytic activity was found with the low-dose surfactant and was abolished with rhCC10. MMP-7 was reduced (p<0.05) with rhCC10 administration, independent of surfactant dose.


CONCLUSIONS
Intratracheal administration of the anti-inflammatory rhCC10 resulted in preserved lung structure and MMP/TIMP profile after 4 h of mechanical ventilation, in a surfactant dose-dependent manner.
Miller
Thomas L
TL
Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, and Nemours Research Lung Center, Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
Shashikant
Beth N
BN
Pilon
Aprile L
AL
Pierce
Richard A
RA
Shaffer
Thomas H
TH
Wolfson
Marla R
MR
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008171:Lung Diseases / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020783:Matrix Metalloproteinase 7 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D011817:Rabbits; D011994:Recombinant Proteins; D012121:Respiration, Artificial / Q000009:adverse effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D014132:Trachea / Q000187:drug effects; D014598:Uteroglobin / Q000008:administration & dosage*
D000893:Anti-Inflammatory Agents; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014598:Uteroglobin; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9