50 mmHg) and 1 min before resuscitation showed attenuation of the increases in the serum levels of markers of MODS normally observed in this model. Severe disruption of the architecture of tissues and the extensive cellular infiltration into those tissues were also largely inhibited in animals that received HDLs. Human HDLs attenuate the MODS associated with ischemia and reperfusion injury after hemorrhagic shock in rats.—Cockerill, G. W., McDonald, M. C., Mota-Filipe, H., Cuzzocrea, S., Miller, N.E., Thiemer- mann, C. High density lipoproteins reduce organ injury and organ dysfunction in a rat model of hemorrhagic shock.
A common cause of circulatory shock is severe blood loss associated with trauma. Despite improvements in intensive care medicine, mortality from hemorrhagic shock (HS) remains high (1, 2). Thus, there is a great need for new approaches to improve therapy and the outcome of patients with HS (2). In clinical practice, HS leads to a delayed vascular decompensation (result- ing in severe hypotension) and, in ;25% of patients, in the dysfunction or failure of several organs including lung, kidney, gut, liver, and brain (3). There is evidence
that both ischemia (due to reduced blood and oxygen supply during hemorrhage) and reperfusion (during resuscitation) play an important role in the pathophys- iology of the multiple organ dysfunction syndrome (MODS) in HS (4).
In both experimental and clinical studies, local or generalized ischemia (followed by reperfusion) re- sulted in increased vascular permeability leading to protein leakage, formation of noncardiogenic interstitial edema, and the accumulation of neutrophils in all organs (5– 8). The infiltration of neutrophils into tis- sues is determined largely by interplay between cyto- kines, chemokines, and adhesion molecules (9). Sev- eral lines of evidence suggest that adhesion blockade may be a useful therapeutic approach (10, 11). Al- though the precise factors leading to MODS have not been identified (12), the rapid increase of cytokines and adhesion molecules very early after trauma and hemorrhage and the rapid decrease in interleukin 10 (IL-10) in patients who develop MODS (13) suggest a loss of anti-inflammatory potency.
Plasma high density lipoproteins (HDLs) are a family of mostly spheroidal particles of density 1.063–1.21 g/ml. As they are smaller than other lipoproteins, they penetrate between the endothelial cells more readily, producing relatively high concentrations in tissue fluids (14). The major apolipoprotein (apo) of almost all plasma HDLs is apo A-I, which in association with phospholipids and cholesterol encloses a core of cho- lesteryl esters. Nascent (i.e., newly synthesized) HDLs secreted by liver and intestine contain no cholesteryl esters, and are discoidal. A negative association of plasma HDL concentration with coronary artery disease has been documented from epidemiologic studies (15–17). Experiments in animals have demonstrated that HDLs have direct anti-atherogenic activity (18 –21).
We have shown that HDLs are able to inhibit cyto- kine-induced expression of adhesion molecules and that their anti-inflammatory properties are also ob- served in animal models (22–24). In this study, we investigated the hypothesis that systemic administration of HDLs will exert beneficial effects in animal models of HS. We have examined the effects of native high density lipoproteins (nHDLs) and reconstituted high density lipoproteins (recHDLs) on the organ injury and failure caused by severe hemorrhage and resusci- tation in rats, particularly the effects of nHDLs and recHDLs on renal dysfunction and liver, pancreatic, intestinal, and lung injury associated with HS. To gain better insight into the mechanism of the beneficial effects of HDLs observed in this model, we also inves- tigated their effects on 1) adhesion and transmigration of polymorphonuclear leukocytes (PMNs) and 2) cyto- kine-induced synthesis of IL-8 in human umbilical vein endothelial cells (HUVECs) in vitro and the rat IL8 homologue macrophage inflammatory protein 2 (MIP-2) in rats in vivo. We also investigated the effects of HDLs on the expression of ICAM-1 and P-selectin in the kidney and intestine of rats subjected to shock.