Effects of recombinant Clara cell secretory protein (rhCC10) on inflammatory-related matrix metalloproteinase activity in a preterm lamb model of neonatal respiratory distress.
OBJECTIVE
To test the hypothesis that recombinant Clara cell secretory protein (rhCC10) instillation would foster improved lung function, acute structural preservation, and attenuation of matrix metalloproteinase (MMP) activity in a surfactant-deficient, mechanically ventilated lung.


METHODS
Interventional laboratory study.


METHODS
An academic medical research facility in the northeastern United States.


METHODS
Sedated, ventilated premature lambs.


METHODS
Preterm lambs (n = 18; 126 +/- 3 days gestation) were instrumented, ventilated, and treated with 100 mg/kg exogenous surfactant. Lambs were randomized to receive 0, 0.5, or 5.0 mg/kg rhCC10 (n = 6 per group) and were ventilated for 4 hrs.


RESULTS
Posttreatment, lung function and cardiopulmonary stability were monitored for the ventilation period and then animals were killed for in vitro surfactant function analysis, lung histomorphometry, and analysis of MMP-2, -7, and -9 as well as their tissue inhibitors (TIMP)-1 and -2. Ventilation efficiency and pulmonary compliance were improved in the 5.0-mg/kg rhCC10 group by 4 hrs. Lung expansion was variable in the apical regions only. MMP-2 quantity was greater in the apical than the base lung regions of rhCC10-treated groups, and rhCC10 decreased MMP-7 in the base of the lung.


CONCLUSIONS
These data suggest that improved lung function in the surfactant-treated preterm lamb following intratracheal rhCC10 may be related to the reduction of proteolytic activity of MMP-7.
Miller
Thomas L
TL
Department of Physiology, Temple University School of Medicine, Philadelphia, PA, USA.
Shashikant
Beth N
BN
Pilon
Aprile L
AL
Pierce
Richard A
RA
Shaffer
Thomas H
TH
Wolfson
Marla R
MR
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000473:pathology; D008170:Lung Compliance; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011480:Protease Inhibitors / Q000032:analysis; D011650:Pulmonary Alveoli / Q000473:pathology; D011663:Pulmonary Surfactants / Q000627:therapeutic use; D012121:Respiration, Artificial; D012127:Respiratory Distress Syndrome, Newborn / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D012756:Sheep; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D016896:Treatment Outcome; D014598:Uteroglobin / Q000008:administration & dosage / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D011663:Pulmonary Surfactants; C556389:SCGB1A1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D014598:Uteroglobin; D045726:Metalloproteases