ARDS-like lung injury produced by endotoxin in platelet-activating factor-primed rats

Abstract

We recently reported that the combined administration of lipopolysaccharide (LPS) and platelet-activating factor (PAF) in rats, at doses that are completely devoid of any effect when given alone, caused lung injury characterized by neutrophil adhesion to lung capillaries and postcapillary venules, neutrophil accumulation in the lung parenchyma, platelet-fibrin deposits in postcapillary venules, and pulmonary edema. A marked increase in lung myeloperoxidase activity and an elevation of serum tumor necrosis factor-alpha and thromboxane B2, along with leukopenia and thrombocytopenia, were also noticed. The present study aimed to examine whether repeated LPS-PAF stimulus can cause progressive lung injury reminiscent of adult respiratory distress syndrome (ARDS). A second LPS-PAF challenge, 4 h (n = 11) after the original challenge, induced mortality (69% at 24 h, P < 0.01) and some of the pathological changes seen in clinical ARDS, including severe pulmonary edema, alveolar proteinaceous exudates, monocytic infiltration, and a further increase in lung myeloperoxidase activity (700%, P < 0.01). Repeated LPS-PAF dosing also resulted in sustained increased serum tumor necrosis factor-alpha levels (1,610 +/- 470 pg/ml, P < 0.01) and further exacerbation of the leukopenia (-68 +/- 6%, P < 0.01) and thrombocytopenia (-65 +/- 8%, P < 0.01). These data suggest that repeated LPS-PAF actions are sufficient to elicit pathophysiology of ARDS-like lung injury.

Amantadine inhibits platelet-activating factor induced clathrin-mediated endocytosis in human neutrophils

“…PMNs then diapedese through the EC, which involves CD31 on both PMNs and EC, chemotax to the site of infection, and phagocytize and kill the pathogenic invaders (1,6,22,24,74). Furthermore, priming changes the PMN phenotype to "hyperresponsive," such that the PMNs microbial arsenal can be activated by normally innocuous stimuli (74), and in two-event models of PMN-mediated lung injury, PMN priming agents are etiologic; therefore, interruption of the priming signal can ameliorate or inhibit tissue damage (49,61).…”

“…Platelet-activating factor (PAF) is an effective physiological priming agent, and its receptor is a member of the G proteincoupled receptor family (GPCR) (37,49,58,67). A characteristic of GPCRs is clathrin-mediated endocytosis (CME), which may be sensitive to weak bases such as amantadine (33).…”

Genetics reveals importance of platelet activating factor in asthma and possibly other inflammatory states.

“…PAF has been implicated as a mediator in adult experimental respiratory distress syndrome (ARDS), especially due to bacteremia (5). In experimental ischemia-induced reperfusion injury, PAF receptor antagonists have been shown to reduce lung injury after cardiopulmonary bypass (6).…”

Lower tidal volumes for everyone: principle or prescription?

“…For example, marathon athletes may repeatedly take breaths exceeding 2 l ([20 ml/kg) for hours on end without apparent problems afterward. Patients at risk of ARDS may be predisposed to injurious responses to considerably lower tidal volumes by reduced aerated reservoir (functional residual capacity, FRC), stress focusing at points of mechanical heterogeneity [6], and by tissues primed for inflammation by the first hit of their underlying disease [7,8]. Yet, until the airspace begins to flood or consolidate, the aeratable space is seldom reduced by more than half, and when precautions are taken to avoid fully horizontal positioning and to apply modest PEEP, tidal re-opening and closure risk is reduced considerably.…”