Unfractionated heparin and enoxaparin reduce high-stretch ventilation augmented lung injury: a prospective, controlled animal experiment.
BACKGROUND
Dysregulation of coagulation and local fibrinolysis found in patients with acute lung injury often results in the need for the support of mechanical ventilation. High-tidal-volume mechanical ventilation can increase lung damage and suppression of fibrinolytic activity, but the mechanisms are unclear. We hypothesized that subcutaneous injections of unfractionated heparin and enoxaparin would decrease neutrophil infiltration, lung edema, and plasminogen-activator inhibitor-1 (PAI-1) production in mice exposed to high-tidal-volume ventilation.


METHODS
Male C57BL/6 mice, weighing 20 to 25 g, were exposed to either high-tidal-volume (30 ml/kg) or low-tidal-volume (6 ml/kg) mechanical ventilation with room air for 1 to 5 hours after 200 IU/kg or 400 IU/kg unfractionated heparin and 4 mg/kg or 8 mg/kg enoxaparin administration. Nonventilated mice served as a control group. Evan blue dye, lung wet- to dry-weight ratio, histopathologic grading of epithelium, myeloperoxidase, and gene expression of PAI-1 were measured. The expression of PAI-1 was studied by immunohistochemistry.


RESULTS
High-tidal-volume ventilation induced increased microvascular permeability, neutrophil influx, PAI-1 mRNA expression, production of PAI-1 protein, and positive staining of PAI-1 in epithelium in a dose-dependent manner. Lung injury induced by high-tidal-volume ventilation was attenuated with PAI-1-deficient mice and pharmacologic inhibition of PAI-1 activity by low-dose unfractionated heparin and enoxaparin.


CONCLUSIONS
We conclude that high-tidal-volume mechanical ventilation increased microvascular permeability, neutrophil influx, lung PAI-1 mRNA expression, production of active PAI-1. The deleterious effects were attenuated by low-dose unfractionated heparin or enoxaparin treatment. Understanding the protective mechanism of unfractionated heparin and enoxaparin related to the reduction of PAI-1 may afford further knowledge of the effects of mechanical forces in the lung and development of possible therapeutic strategies involved in acute lung injury.
Li
Li-Fu
LF
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan, Republic of China. lfp3434@adm.cgmh.org.tw
Huang
Chung-Chi
CC
Lin
Horng-Chyuan
HC
Tsai
Ying-Huang
YH
Quinn
Deborah A
DA
Liao
Shuen-Kuei
SK
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001483:Base Sequence; D001834:Body Water; D017931:DNA Primers; D017984:Enoxaparin / Q000494:pharmacology / Q000627:therapeutic use*; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D000925:Anticoagulants; D017931:DNA Primers; D017984:Enoxaparin; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D006493:Heparin