Τίτλος:
Inhibition of HMGCoA reductase by simvastatin protects mice from
injurious mechanical ventilation
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background: Mortality from severe acute respiratory distress syndrome
exceeds 40% and there is no available pharmacologic treatment.
Mechanical ventilation contributes to lung dysfunction and mortality by
causing ventilator-induced lung injury. We explored the utility of
simvastatin in a mouse model of severe ventilator-induced lung injury.
Methods: Male C57BL6 mice (n = 7/group) were pretreated with simvastatin
or saline and received protective (8 mL/kg) or injurious (25 mL/kg)
ventilation for four hours. Three doses of simvastatin (20 mg/kg) or
saline were injected intraperitoneally on days -2, -1 and 0 of the
experiment. Lung mechanics, (respiratory system elastance, tissue
damping and airway resistance), were evaluated by forced oscillation
technique, while respiratory system compliance was measured with
quasi-static pressure-volume curves. A pathologist blinded to treatment
allocation scored hematoxylin-eosin-stained lung sections for the
presence of lung injury. Pulmonary endothelial dysfunction was
ascertained by bronchoalveolar lavage protein content and lung tissue
expression of endothelial junctional protein Vascular Endothelial
cadherin by immunoblotting. To assess the inflammatory response in the
lung, we determined bronchoalveolar lavage fluid total cell content and
neutrophil fraction by microscopy and staining in addition to
Matrix-Metalloprotease-9 by ELISA. For the systemic response, we
obtained plasma levels of Tumor Necrosis Factor-a, Interleukin-6 and
Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was
undertaken using one-way analysis of variance and Tukey’s post hoc
tests.
Results: Ventilation with high tidal volume (HVt) resulted in
significantly increased lung elastance by 3-fold and decreased lung
compliance by 45% compared to low tidal volume (LVt) but simvastatin
abrogated lung mechanical alterations of HVt. Histologic lung injury
score increased four-fold by HVt but not in simvastatin-pretreated mice.
Lavage pleocytosis and neutrophilia were induced by HVt but were
significantly attenuated by simvastatin. Microvascular protein
permeability increase 20-fold by injurious ventilation but only 4-fold
with simvastatin. There was a 3-fold increase in plasma Tumor Necrosis
Factor-a, a 7-fold increase in plasma Interleukin-6 and a 20-fold
increase in lavage fluid Matrix-Metalloprotease-9 by HVt but simvastatin
reduced these levels to control. Lung tissue vascular endothelial
cadherin expression was significantly reduced by injurious ventilation
but remained preserved by simvastatin.
Conclusion: High-dose simvastatin prevents experimental hyperinflation
lung injury by angioprotective and anti-inflammatory effects.
Συγγραφείς:
Manitsopoulos, Nikolaos
Orfanos, Stylianos E.
Kotanidou,
Anastasia
Nikitopoulou, Ioanna
Siempos, Ilias
Magkou,
Christina
Dimopoulou, Ioanna
Zakynthinos, Spyros G. and
Armaganidis, Apostolos
Maniatis, Nikolaos A.
Περιοδικό:
BMJ Open Respiratory Research
Εκδότης:
BioMed Central Ltd.
Λέξεις-κλειδιά:
Ventilator lung injury; Acute respiratory distress syndrome; Acute lung
injury; Pulmonary edema; Statin; Lung function; Lung compliance;
Endothelial permeability
DOI:
10.1186/s12931-015-0173-y
