sábado, 20 de marzo de 2010

High density lipoproteins reduce organ injury and organ dysfunction in a rat model of hemorrhagic shock

High density lipoproteins  reduce  organ injury and organ dysfunction  in a rat model  of hemorrhagic shock

 High density lipoproteins (HDLs) inhibit the cytokine-induced expression of endothelial cell adhesion molecules both in vitro and in vivo. We examined  the ability of HDLs to mediate a functional anti-inflammatory effect  by measuring their ability to prevent  neutrophil   adhesion   and  transmigration  in vitro.  Treatment  of  human  endothelial  cell  cultures with physiologic concentrations of HDLs inhibited neu- trophil  binding  by 68  6 5.9% (mean  and  SE,  n56, P<0.05) and neutrophil transmigration by 48.7 6 6.7% (n58, P<0.05). We then examined the effect  of HDLs on  inflammatory infiltration and subsequent  multiple organ dysfunction syndrome (MODS), associated with trauma in a rat model of hemorrhagic shock. Rats given human HDLs  (80  mg apo  A-I/kg,  i.v.)  90  min after hemorrhage (which reduced mean arterial pressure to
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.
Maria Gabriela Medina Medina
C.I. 16779553

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