Intrapulmonary application of a 5-lipoxygenase inhibitor using surfactant as a carrier reduces lung edema in a piglet model of airway lavage.
Leukotriene-generated effects on microvascular integrity and polymorphonuclear leukocytes (PMNL) play a key role in the inflammatory process of the alveolar-capillary unit in neonatal acute respiratory distress syndrome. We asked if intrapulmonary application of MK886, a 5-lipoxygenase inhibitor, and the use of a porcine surfactant preparation (Curosurftrade mark) as a carrier substance would improve lung function in a neonatal piglet model of airway lavage. Anesthetized, mechanically ventilated newborn piglets (n = 19) underwent repeated airway lavage to induce acute lung injury. Piglets then received either surfactant alone (S, n = 6), or MK886 admixed with surfactant (S + MK, n = 7), or an air-bolus injection as control (C, n = 6). Measurements of gas exchange, lung function, extravascular lung water (EVLW), cell counts, and leukotriene B(4) (LTB(4)) concentrations in bronchoalveolar lavage fluid (BAL) were performed during 6 hr of mechanical ventilation. Arterial oxygen partial pressure (PaO(2)) (S, 13.8 +/- 4.2 kPa, vs. S + MK, 20 +/- 6.6; P < 0.05), functional residual capacity (S, 15.1 +/- 6.8 ml/kg, vs. S + MK, 18.8 +/- 3.7 ml/kg; P < 0.05), and EVLW (S, 29 +/- 14 ml/kg, vs. S + MK 24 +/- 4 ml/kg; P < 0.05) were significantly improved in the MK886 group. This clinical effect was linked with a decrease in LTB(4) concentration in BAL (S, 3.5 (1.9-5.4) pg/ml, vs. S + MK, 1.6 (0.7-4.7) pg/ml; P < 0.05) and an increase in IL-8 (S, 2,103 (852-4,243) pg/ml, vs. S + MK, 3,815 (940-26,187) pg/ml; P < 0.05). PMNL counts in BAL were reduced (S, 570 +/- 42 cells/ml, vs. 275 +/- 35 cells/ml; P < 0.05). In conclusion, intrapulmonary application of the 5-lipoxygenase inhibitor MK886 with surfactant as a carrier improves lung function by decreasing EVLW as the main response to LTB(4) reduction.
Department of Pediatrics, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany. ankermann@pediatrics.uni-kiel.de
Tobias
T
Ankermann
Anja
A
Reisner
Tina
T
Wiemann
Heike
H
Koehler
Matthias
M
Krams
Martin F
MF
Krause
D000818:Animals; D000831:Animals, Newborn; D001688:Biological Products; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D007231:Infant, Newborn; D016209:Interleukin-8 / Q000032:analysis; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010743:Phospholipids; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000517:prevention & control; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D012121:Respiration, Artificial; D012127:Respiratory Distress Syndrome, Newborn / Q000503:physiopathology; D013552:Swine; D002722:Chlorobenzenes
D001688:Biological Products; D007211:Indoles; D016209:Interleukin-8; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D010743:Phospholipids; C060893:MK-886; D002722:Chlorobenzenes; C068291:poractant alfa