Oxidized phospholipids reduce ventilator-induced vascular leak and inflammation in vivo.
BACKGROUND
Mechanical ventilation at high tidal volume (HTV) may cause pulmonary capillary leakage and acute lung inflammation resulting in ventilator-induced lung injury. Besides blunting the Toll-like receptor-4-induced inflammatory cascade and lung dysfunction in a model of lipopolysaccharide-induced lung injury, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exerts direct barrier-protective effects on pulmonary endothelial cells in vitro via activation of the small GTPases Rac and Cdc42. To test the hypothesis that OxPAPC may attenuate lung inflammation and barrier disruption caused by pathologic lung distension, we used a rodent model of ventilator-induced lung injury and an in vitro model of pulmonary endothelial cells exposed to pathologic mechanochemical stimulation.


METHODS
Rats received a single intravenous injection of OxPAPC (1.5 mg/kg) followed by mechanical ventilation at low tidal volume (LTV) (7 mL/kg) or HTV (20 mL/kg). Bronchoalveolar lavage was performed and lung tissue was stained for histological analysis. In vitro, the effects of OxPAPC on endothelial barrier dysfunction and GTPase activation were assessed in cells exposed to thrombin and pathologic (18%) cyclic stretch.


RESULTS
HTV induced profound increases in bronchoalveolar lavage and tissue neutrophils and in lavage protein. Intravenous OxPAPC markedly attenuated HTV-induced protein and inflammatory cell accumulation in bronchoalveolar lavage fluid and lung tissue. In vitro, high-magnitude stretch enhanced thrombin-induced endothelial paracellular gap formation associated with Rho activation. These effects were dramatically attenuated by OxPAPC and were associated with OxPAPC-induced activation of Rac.


CONCLUSIONS
OxPAPC exhibits protective effects in these models of ventilator-induced lung injury.
Nonas
Stephanie
S
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Birukova
Anna A
AA
Fu
Panfeng
P
Xing
Jungjie
J
Chatchavalvanich
Santipongse
S
Bochkov
Valery N
VN
Leitinger
Norbert
N
Garcia
Joe G N
JG
Birukov
Konstantin G
KG
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D017097:Electric Impedance; D008297:Male; D010713:Phosphatidylcholines / Q000627:therapeutic use*; D010743:Phospholipids / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011914:Rats, Inbred BN; D012121:Respiration, Artificial / Q000009:adverse effects*
D016207:Cytokines; D010713:Phosphatidylcholines; D010743:Phospholipids; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine