Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: correlation with lung surfactant protection.
OBJECTIVE
We attempted to determine whether group IIA secretory phospholipase A2 (sPLA2-IIA) blockade after the onset of lung injury exerted therapeutic efficacy in the treatment of oleic acid (OA)-induced acute lung injury by using S-5920/LY315920Na, a novel specific inhibitor of sPLA2-IIA, with special interest in the changes of lung surfactant.


METHODS
Prospective animal study.


METHODS
University laboratory.


METHODS
Forty Japanese white rabbits.


METHODS
The rabbits, under anesthesia, were endotracheally intubated and mechanically ventilated and then were divided into the following groups: OA + vehicle groups, intravenous infusion of OA for the first 2 hrs (0.1 mL x kg(-1) x hr(-1)) with the addition of vehicle (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); OA + S-5920/LY315920Na groups, treated identically to the OA control with the addition of S-5920/LY315920Na (1 mg/kg bolus followed by infusion at 0.5 mg x kg(-1) x hr(-1)) after OA (1 or 2 hrs after OA administration, each n = 9, total 18 rabbits); saline control groups, treated with saline instead of OA with the addition of vehicle (1 hr after OA administration, 4 rabbits). Arterial blood gas, lung mechanics, lung inflammation, lung surfactant phospholipids, and production of inflammatory mediators in the lung were measured.


RESULTS
Treatment with S-5920/LY315920Na 1 hr after OA infusion, but not 2 hrs after infusion, significantly attenuated the lung injury, as estimated by hypoxemia, decreased lung compliance, pulmonary edema, and vascular permeability. The therapeutic efficacy was similar to that found in our previous pretreatment study. The treatment after 1 hr dramatically inhibited OA-induced surfactant degradation in the bronchoalveolar lavage fluid (BALF), without affecting the concentrations of thromboxane A2, leukotriene B4, and interleukin-8 in BALF. The degree of surfactant degradation in BALF paralleled well with the severity of the lung injury. Furthermore, recombinant human sPLA2-IIA reproduced the similar hydrolysis pattern of isolated surfactant in vitro, which was inhibited by S-5920/LY315920Na.


CONCLUSIONS
Our results indicate that therapeutic blockade of sPLA2-IIA ameliorated lung dysfunction via protection of surfactant degradation in an animal model of acute lung injury, and they suggest a new strategy in treating clinical acute lung injury.
Furue
S
S
Discovery Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Mikawa
K
K
Nishina
K
K
Shiga
M
M
Ueno
M
M
Tomita
Y
Y
Kuwabara
K
K
Teshirogi
I
I
Ono
T
T
Hori
Y
Y
Matsukawa
A
A
Yoshinaga
M
M
Obara
H
H
D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D054501:Group II Phospholipases A2; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007651:Keto Acids; D008297:Male; D019301:Oleic Acid / Q000633:toxicity; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011663:Pulmonary Surfactants / Q000187:drug effects; D011817:Rabbits; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy*
D000085:Acetates; D004791:Enzyme Inhibitors; D007211:Indoles; D007651:Keto Acids; D011663:Pulmonary Surfactants; C117948:varespladib; D019301:Oleic Acid; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2