International Journal of Infectious Diseases
Volume 14, Issue 10 , Pages e857-e867, October 2010

Pathogenesis of the hyperlipidemia of Gram-negative bacterial sepsis may involve pathomorphological changes in liver sinusoidal endothelial cells

  • Rajkumar Cheluvappa

      Affiliations

    • Department of Medicine, St. George Clinical School and Centre for Infection and Inflammation Research, School of Medical Sciences, Wallace Wurth Building, University of New South Wales, Gate 9 High Street, Sydney, NSW 2052, Australia
    • Corresponding Author InformationCorresponding author. Tel.: +61 0406 0406 20; fax: +61 02 9385 1389.
    • ,
  • Gerene M. Denning

      Affiliations

    • Department of Emergency Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
    • ,
  • Gee W. Lau

      Affiliations

    • Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
    • ,
  • Michael C. Grimm

      Affiliations

    • Department of Medicine, St. George Clinical School and Centre for Infection and Inflammation Research, School of Medical Sciences, Wallace Wurth Building, University of New South Wales, Gate 9 High Street, Sydney, NSW 2052, Australia
    • ,
  • Sarah N. Hilmer

      Affiliations

    • Centre for Education and Research on Aging and ANZAC Research Institute, University of Sydney and Concord RG Hospital, Concord, New South Wales, Australia
    • Departments of Aged Care and Clinical Pharmacology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
    • ,
  • David G. Le Couteur

      Affiliations

    • Centre for Education and Research on Aging and ANZAC Research Institute, University of Sydney and Concord RG Hospital, Concord, New South Wales, Australia

Received 8 May 2009; received in revised form 30 November 2009; accepted 25 February 2010. published online 08 July 2010.

Corresponding Editor: William Cameron, Ottawa, Canada

Article Outline

Summary 

The Gram-negative bacterium Pseudomonas aeruginosa is one of the most common opportunistic pathogens, especially after liver transplantation. Pathophysiological alterations of liver sinusoidal endothelial cells (LSECs) have far-reaching repercussions on the liver and on metabolism. LSECs are perforated with fenestrations, pores that facilitate the transfer of lipoproteins and macromolecules between blood and hepatocytes. Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) and the P. aeruginosa toxin, pyocyanin, have marked effects on LSECs. Initial loss of LSEC porosity (defenestration) induced by P. aeruginosa pyocyanin and LPS may confer subsequent immune tolerance to circulating bacterial antigens and toxins. This review collates the known immune responses of the liver to Gram-negative bacterial toxins, with a focus on LSECs. Hyperlipidemia is an important response to Gram-negative bacterial sepsis. The mechanisms proposed for sepsis-associated hyperlipidemia include tissue lipoprotein lipase inhibition and upregulated hepatic triglyceride production. In this review, we propose defenestration of the LSECs by bacterial toxins as an additional mechanism for the hyperlipidemia of sepsis. Given the role of LSECs in hyperlipidemia and liver allograft rejection, LSEC changes induced by P. aeruginosa toxins including LPS and pyocyanin may have significant clinical implications.

Keywords: Liver sinusoidal endothelial cell fenestrations, Transplantation, Pseudomonas aeruginosa Pyocyanin, Oxidative stress, Electron microscopy, Immunohistochemistry

 

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1. Introduction 

Pathologic and morphologic alterations of the liver sinusoidal endothelial cell (LSEC) have far-reaching repercussions for the liver and for systemic metabolism because of its strategic position in the liver sinusoid. LSECs are perforated with fenestrations, which are pores that facilitate the transfer of lipoproteins and macromolecules between the blood and hepatocytes. Loss of LSEC porosity is termed defenestration, which can result from loss of fenestrations with or without decreases in fenestration diameter. Sepsis is associated with hyperlipidemia, and mechanisms proposed include inhibition of tissue lipoprotein lipase and increased triglyceride production by the liver. However, LSECs have also been increasingly recognized to play a significant role in hyperlipidemia. Pertaining to this important role, Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) and Pseudomonas aeruginosa pyocyanin have marked and diverse effects on LSEC morphology and function. Additionally, conditions presenting with LSEC defenestration such as aging and bacterial infections are associated with impaired lipoprotein and chylomicron remnant uptake by the liver and hyperlipidemia.

P. aeruginosa infection is an increasingly important cause of sepsis and death in organ transplant recipients, particularly those receiving liver transplants126, 176. P. aeruginosa has a special affinity for tissue vasculature, typically surrounding blood vessels circumferentially (perivascular cuffing) during infection1, 2 or congregating in postcapillary venules.3 In vitro studies show that P. aeruginosa induces apoptosis in the cultured endothelial cell line ECV304,4, 5 suggesting that it might also contribute to loss of endothelium in vivo.

P. aeruginosa produces a number of virulence factors including pyocyanin, a tricyclic phenazine derivative with a broad activity spectrum including redox activity6, 7 with production of reactive oxygen species (ROS),8 immunomodulatory9, 10 and pro-inflammatory effects,11 inactivation of succinic dehydrogenase,12 cytotoxicity,6, 11 and induction of apoptosis13 and senescence.14 Pyocyanin induces oxidative stress and morphological changes in endothelial cells.15, 16 Hepatic LSECs are sensitive to both oxidative stress17 and the effects of LPS18, 19 and pyocyanin.16, 20 Owing to the role of the LSEC in liver allograft rejection21 and hyperlipidemia,22, 23 cellular and biochemical changes induced by Gram-negative bacterial toxins may have significant clinical import.

This review collates the known immune responses of the liver to Gram-negative bacterial toxins, with a focus on LSECs, and summarizes up-to-date information on LSECs in relation to the cellular pathogenesis of LPS and P. aeruginosa toxins in inducing sepsis-related hyperlipidemia in Gram-negative bacterial sepsis.

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2. The liver lobule and LSECs 

The lobule is the structural and functional unit of the liver. Each lobule consists of parenchyma with hepatocytes supplied by the smallest portal tracts containing portal vein radicles, hepatic arterioles, and bile ductules (Figure 1). The portal tract for each lobule is called the portal triad. The hepatic sinusoids that carry blood from the hepatic portal vein and the hepatic artery emanate from the portal triad and radiate outwards. The hepatocytes are drained by the central veins, also called terminal hepatic veins. The hepatocytes surrounding the portal triads (periportal area, zone 1) are supplied with oxygenated blood, and are more resistant to hypoxia and ischemic injury than the hepatocytes distributed around the central veins (pericentral area, zone 3).

  • View full-size image.
  • Figure 1. 

    Hepatic microcirculation and the liver sinusoid. Structure of the liver sinusoid:187 (A) Scanning electron micrograph of a vascular cast of the hepatic microcirculation and sinusoids showing a branch of the portal vein (PV) and branch of the hepatic artery (HA) with surrounding sinusoidal microvascular network (S). A branch from the PV into the sinusoids is shown (↑). (B) Scanning electron micrograph of liver; Kupffer cell (KC) lying in a sinusoid. (C) Transmission electron micrograph of liver; the liver sinusoidal endothelial cell (LSEC) layer is thin and perforated with fenestrations (F). The extension of a stellate cell (HSC) lies beneath the liver sinusoidal endothelial cell.

Four types of cells constitute the hepatic sinusoid, LSECs, Kupffer cells (KCs), stellate cells (SCs), and pit cells, each with specific morphology and function (Figure 1). LSECs make up approximately 20% of hepatic cells, KCs around 15%, and SCs around 5%. Depending on the disease process, each cell type can undergo specific changes.24

LSECs, which line the liver sinusoidal capillary lumen, regulate the passage of substances to and fro from the blood. KCs, which are modified macrophages attached to the endothelium, phagocytose and degrade gastrointestinal particles with antigenic components as well as bacteria and toxins that are carried via the portal vein to the liver.25, 26 KCs also assist in tissue repair and clearance of senescent and damaged erythrocytes, and are involved in antigen presentation to T and B lymphocytes.27 SCs, which are located in the space of Disse, store fat and vitamin A, and probably influence hepatic sinusoidal blood flow and play a major role in the synthesis of extracellular matrix, especially in cirrhotic livers.24 Pit cells, a form of natural killer (NK) cells, possess azurophilic granules and exhibit tumoricidal cytolysis.24

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3. LSECs are a key component of the liver sieve apparatus 

The walls of the hepatic sinusoid are lined by LSECs and lack a basement membrane,24, 28 and possess fenestrations with diameters ranging from 100 to 200nm.24, 29 LSEC fenestrations are visible on electron microscopy as circular or oval perforations arranged in sieve plates within the thin extensions of the cytoplasm30 (Figure 1). Both fenestrations and sieve plates are structurally delineated by cytoskeleton elements.31 The subendothelial space that lies between the sinusoids and hepatocytes is called the space of Disse and contains a low-density matrix of basement membrane constituents and SCs (Figure 1). The LSECs, which contain fenestrations arranged in sieve plates, and the subendothelial space of Disse, containing extracellular matrix, together constitute the liver sieve. Since LSECs have fenestrations and lack basement membrane, substrates from the sinusoidal lumen can translocate directly through the fenestrations to the low-density matrix of the space of Disse, to make contact with hepatocyte microvilli, and vice versa.24, 32 Blood constituents that are too large to pass through fenestrations such as erythrocytes and chylomicrons are excluded from the space of Disse, while smaller molecules including smaller lipoproteins such as chylomicron remnants are able to pass directly through the fenestrations.33

LSEC porosity is determined by fenestration frequency (F/μm2) and fenestration diameter. The total area covered by the fenestrations has been estimated to account for approximately 10% of the LSEC surface area.33 The natural porosity of the hepatic sinusoids increases from the portal triad (zone 1) towards the central vein (zone 3) owing to a slight increase in fenestration frequency,34, 35 and perhaps also an increase in fenestration diameter.34, 36 Vidal-Vanaclocha and Barbera-Guillem classified fenestrations into two types, clustered pores, which are more prevalent in the pericentral sinusoids, and free pores, which are more prevalent in the periportal sinusoids.36

Utilizing ‘endothelial massage’, erythrocytes and leukocytes may flush plasma through the fenestrations in the endothelium.29 Permeation selectivity of different molecules is regulated by the fenestration sizes, the molecule sizes, and the transport kinetics of the molecules relative to steric and frictional properties of the fenestrations. Therefore, passage of small sized particles like albumin (7nm diameter) is probably not size-limited in the normal liver. However, passage of larger molecules like IgM antibodies (10–20nm diameter) may be size-limited.

Alterations in fenestration diameter or fenestration frequency can affect exchange of plasma across the sinusoidal lumen and the space of Disse, influencing liver function.30 Loss of LSEC porosity is termed defenestration. In specific pathological processes, defenestration occurs along with endothelial thickening and deposition of excessive extracellular matrix in the subendothelial space of Disse. These changes, called capillarization in cirrhosis and pseudocapillarization in aging, pose an impediment to the transfer of many substrates from the sinusoidal lumen to the hepatocytes through the space of Disse.

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4. LSEC fenestration morphology and the role of the cytoskeleton in fenestration formation and regulation 

LSEC fenestrations (Figure 1) are inducible structures and the cytoskeleton is involved in their formation.37, 38 Each fenestration is circumscribed by a filamentous, fenestration-associated cytoskeleton ring composed of actomyosin components39 with an average filament thickness of around 16nm.31 The sieve plates, which enclose the fenestrations, are encircled by microtubules. The sieve plates and the fenestrations are then linked to the cellular cytoskeleton. Agents that alter the sieve plate structure and porosity induce cytoskeletal changes and vice versa.38

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5. Effect of endobiotics, xenobiotics, and pathophysiological processes on LSEC fenestrations and liver sinusoidal endothelial porosity 

Some endogenous and exogenous agents and pathophysiological conditions that alter LSEC fenestrations are summarized in Table 1.

Table 1. Effect of commonly exposed agents and pathogenic processes on liver sinusoidal endothelial cell fenestrations
Treatment agentPorosity %Fenestration diameterFenestration frequencyOther changesRef.
Autonomic and vasoactive agent regulation
1Acetylcholine ↑ 40, 41
2Noradrenaline ↓ 40, 41
35-Hydroxytryptamine (serotonin)↓↓ ↑ Cell Ca2+, ↑ cAMP changes blocked by Ca2+ chelation or Ca2+ channel blocker38, 42
4Endothelin 1 ↓ 171
5ETA-R antagonist (BQ123) ↓↓ 172
6Prostaglandin E1 ↑ 171
7Pantethine↑↑↑ 173

Alcohol or nicotine exposure
8Ethanol↑↑↑ 38, 45, 46, 47, 48
9Ethanol (chronic)↓ ↓Hepatic steatosis48, 49
10Nicotine↓↓–Hypercholesterolemia52

Exposure to agents present occasionally in the environment
11Dimethylnitrosamine (processed meat)↓ 32
12Poloxamer 407 (various products)↓ ↓No ATP changes, no mitochondrial dysfunction53

Pathological processes
13Aging↓ ↓↓ Mass, ↓ blood flow, ↑ endothelial thickening, pseudocapillarization23, 61, 62, 64
14Cirrhosis↓ ↓Cirrhotic nodules, ↑ endothelial thickening, capillarization22, 23, 50, 51
15Post-hepatic inferior vena cava occlusion↑↓↑, ↑↑ 56
16Portal hypertension↑ ↑ 57
17Paracetamol overdose ↑ 55

Ca2+, calcium ion; cAMP, cyclic adenosine monophosphate; ETA-R, endothelin receptor type A; ATP, adenosine triphosphate.

5.1. Autonomic regulation and cellular mediators 

Hormones of the autonomic nervous system have effects on LSEC fenestration dimensions. Acetylcholine dilates LSEC fenestrations, while noradrenaline constricts them.40, 41 Serotonin (5-HT) increases intracellular calcium, leading to myosin light chain phosphorylation and constriction of fenestrations.38, 42 Similarly, Ca2+ and adenosine triphosphate (ATP) have been shown to constrict fenestrations, thereby reducing porosity.42, 43, 44 Additionally, the Ca2+–calmodulin–actomyosin system has been implicated in the structural regulation of LSEC fenestrations.39 These findings indicate that fenestration contraction is an active process mediated via LSEC Ca2+.

5.2. Alcohol or nicotine exposure 

Acute and medium-term exposure to alcohol in rats in vivo or in isolated LSECs in vitro is associated with increased diameter, frequency, and porosity of LSEC fenestrations.38, 45, 46, 47, 48 In contrast, with chronic long-term alcohol intake, humans49 and mice48 display LSEC defenestration. It has therefore been speculated that increased transmission of larger chylomicrons across the LSECs with acute and medium-term alcohol consumption may be a crucial step in the pathogenesis of alcoholic hepatic steatosis.47 Alcoholic liver disease can have three overlapping sequential phases, namely hepatic steatosis, alcoholic hepatitis, and cirrhosis. It is possible that following short-term/medium-term alcohol consumption after the steatosis/hepatitis phase where the LSEC porosity is increased, and prior to the cirrhotic phase of alcoholic liver disease where the LSEC porosity is decreased, LSEC defenestration commences. LSEC defenestration has been shown to occur early in the pathogenesis of cirrhosis in patients suffering from chronic alcohol abuse,49 accompanied by hyperlipoproteinemia.50 LSEC defenestration also occurs in animal models of cirrhosis.23, 51

Nicotine decreased LSEC porosity to about 40% of that of control animals and induced hypercholesterolemia.52

5.3. Exposure to environmental agents 

The hepatic carcinogen dimethylnitrosamine, which is found in processed meat, induces defenestration.22 The detergent poloxamer 407 induces loss of LSEC porosity by decreasing the fenestration frequency with no changes in ATP or mitochondrial function, and with marked associated hyperlipidemia.53

5.4. Pathophysiological and toxicological processes 

Cirrhosis and aging are also associated with marked structural changes in the sinusoidal endothelium and the space of Disse that influence bulk plasma transfer into the space of Disse, through the LSECs.23 Capillarization associated with cirrhosis differs from aging-associated pseudocapillarization by having additional features of bridging fibrosis or nodular regeneration, periportal or pericentral fibrosis, loss of hepatocyte microvilli, and only minor deposits of collagen in the space of Disse. These changes impede the transfer of many substrates including chylomicron remnants, albumin, protein-bound drugs, and other macromolecules to the hepatocytes via the space of Disse.54

Paracetamol overdose dilates fenestrations and causes the generation of large gaps.55 Post-hepatic inferior vena cava occlusion markedly dilates fenestration diameter, while decreasing the fenestration frequency.56 Artificial high perfusion pressure through the hepatic portal vein simulating portal hypertension dilates fenestrations, and results in the trapping of large chylomicrons.57 This particular study also suggests a possible mechanism in the hepatic steatosis seen in the ‘nutmeg liver’ of chronic venous congestion.

The vascular and liver sinusoidal endothelial complications of diabetes including LSEC defenestration are well established and are clinically significant.58, 59 With aging, there is a substantial loss of fenestrations in the LSEC,60, 61, 62, 63 which impairs lipoprotein transfer to the hepatocyte.64 Thus there are potential parallels between age-related dyslipidemia and diabetes mellitus-related dyslipidemia.65, 66, 67

Alterations in number, frequency, distribution and diameter of fenestrations by hormones, xenobiotics, hepatotoxins, and diseases have important ramifications for hepatic microcirculation, substrate handling, drug metabolism, and overall function. Chylomicrons (100–1000nm diameter) are too large to pass through the fenestrations.68 Only partially catabolized chylomicrons (chylomicron remnants) attain individual dimensions small enough to pass through the fenestrations into the space of Disse.54, 69 In defenestration caused by cirrhosis,22, 23, 50 normal aging,23, 61, 62, 64 or with treatment with detergents like poloxamer 407,53 distribution of chylomicron remnants was excluded from the space of Disse.53

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6. Immunological functions of the liver: the hepatic immune response to Gram-negative bacterial toxins 

6.1. The liver and gastrointestinal bacterial antigens 

The liver is the first organ that encounters pathogens and pathogen-derived products from the gut. For example, alcohol-induced gut permeability liberates LPS from gastrointestinal Gram-negative bacteria.70 Most Gram-negative bacteria including P. aeruginosa have LPS as a component of their outer cell walls. LPS is present in normal portal blood at concentrations of 10 pg/ml to 1 ng/ml.71 In one study performed on samples from 34 elective abdominal surgery patients, 97% of the patients had LPS in their portal blood, demonstrating that LPS is present normally in portal blood and is not necessarily pathogenic.72 In this study, systemic endotoxemia was observed in three of the four patients who also had liver disease. None of the patients without liver disease had endotoxemia. In cirrhosis, there is augmented LPS uptake by the liver and increased biliary excretion of LPS.73

Immunologically active liver cells include KCs, LSECs, neutrophils, and lymphocytes, and perhaps the hepatocytes themselves.27, 71 The liver also acts as a filter or a ‘sieve’ for bacteria and antigens carried from the gastrointestinal tract. These antigens are phagocytosed and degraded by KCs and LSECs.25 The near complete absence of lymphoid tissue in the liver implies that antigens are degraded here without the production of antibody.27, 71 The antigens are thus precluded from reaching other antibody-producing sites in the body, thereby preventing adverse systemic hypersensitivity. Thus the liver favors the induction of tolerance rather than the induction of immunity.27, 71 Different liver cell types contribute in different ways to induce liver antigenic tolerance. These include control of antigen presentation (immune ignorance), clonal deletion, and immune deviation. Naive T cells are activated by LSECs, but do not differentiate into effector T cells. These T cells demonstrate a functional phenotype and cytokine induction profile typical of tolerance induction.74 Dendritic cells (DCs), LSECs, KCs and hepatocytes also contribute to tolerance induction by deletion of T cells through induction of apoptosis.71 Recently, the mechanical contribution of LSECs in the development of immune tolerance has also been well demonstrated. Resident and circulating lymphocytes make direct contact with hepatocytes via LSEC fenestrations using cytoplasmic extensions.75 Hepatocyte MHC class I and ICAM-1 molecules, which are necessary for T cell activation, have been shown to be polarized on the perisinusoidal side of the hepatocellular membrane apparently to maximize interaction with blood lymphocytes.75 Corroborating this is the fact that LSEC defenestration at an earlier time-point of mouse model of immune-mediated hepatitis significantly attenuates subsequent liver damage in the same model, pointing to LSEC defenestration modifying hepatic immunological responses.76

6.2. KC activation 

KCs are predominantly located in the periportal area. They assist in tissue repair, T and B lymphocyte interaction, and cytotoxic activity in disease processes.77 KCs are antigen presenting cells that modulate immune responses, induce oral tolerance to bacterial superantigens, and suppress T-cell activation by antigen-presenting LSECs, prostanoids, and tumor necrosis factor-α (TNF-α).71, 78 Upon activation, KCs secrete interleukins (IL), chemokines, TNF-α, collagenase, and lysosomal hydrolases. During acute hepatic insult, KCs secrete enzymes and cytokines that damage hepatocytes, and are active in the remodeling of extracellular matrix. Granulocyte-colony stimulating factor (G-CSF) is a negative feedback signal for macrophage-derived TNF-α production after LPS-induced hepatotoxicity.79

Following LPS-stimulation, KCs release IL-6, IL-8, and other chemokines, as well as TNF-α, which induce liver parenchymal damage. These cytokines also stimulate LSECs, SCs, and NK cells to release pro-inflammatory cytokines, thus exacerbating the damage.27 Exposure of KCs to LPS can lead to intense inflammatory mediator production, and subsequently liver injury. KCs are involved in the initial hepatic insult, followed by neutrophils in the latter phase of hepatic injury.80, 81 Both cell types liberate ROS to inflict the injury.81, 82, 83 Alcohol increases gastrointestinal tract permeability, liberating LPS from gut bacteria into the blood stream, which in turn activate KCs. KCs and gastrointestinal tract-derived LPS are crucial in the pathogenesis of alcohol-induced hepatotoxicity.70 Long-term alcohol exposure changes KC sensitivity to LPS.84 TNF-α plays a key role in the pathogenesis of hepatic injury in response to LPS. Leukotriene D4 and ROS precede TNF-α action in the induction of LPS-induced hepatitis in the murine endotoxin/galactosamine TNF-α model.85, 86

6.3. The liver, bacterial antigens and ROS 

Most antioxidant mechanisms are upregulated by LSECs in response to LPS, including H2O2-detoxifying capacity,87 LSEC glutathione (GSH) efflux mechanisms,88 glucose transporter 1 (GLUT1), glucose-6-phosphate dehydrogenase (G6PD),89 superoxide dismutases (SODs), and glutathione peroxidase (GPx).90 Superoxide generation in the hepatic sinusoid in response to LPS challenge is likely to be a factor involved in liver damage.91

6.4. The liver, coagulation system and gastrointestinal bacterial antigens 

In one murine model study, co-administration of non-hepatotoxic doses of the commonly used H2 receptor-blocker ranitidine and LPS activated the clotting system via over-expression of plasminogen-activator inhibitor-1 (PAI-1), with fibrin deposition in the liver and hepatocyte damage.92, 93 Thrombin is a promoter94 and a distal mediator95 of LPS-induced hepatotoxicity. LPS induces decreased LSEC thrombomodulin, which results in sinusoidal microthrombus formation and exacerbation of hepatic injury.96 Platelets97 and the coagulation cascade98 contribute to LPS-induced hepatic injury. KCs play an important role in LPS-induced sinusoidal thrombogenesis, fibrin degradation and deposition.99

6.5. Other hepatic responses to gastrointestinal bacterial antigens 

LPS alters the membrane fluidity of hepatocytes.100 LPS may influence hepatocyte–macrophage communications,101 which in humans may lead to a transient increase in liver insulin-like growth factor in addition to transient increases in cortisol and pituitary growth hormone, similar to changes seen in acute trauma.102 In the isolated perfused rat liver model, LPS induces cholestasis without significant hepatic damage, which suggests a possible role for extrahepatic mechanisms for induction of liver damage.103 LPS is a potent stimulator of hepatocyte fibronectin, which suggests that hepatocytes may also be directly involved in liver fibrosis.104 LPS also synergizes with monocrotaline,105 aflatoxin B1,106 polychlorinated biphenyls,107 and a range of liver toxins like carbon tetrachloride, ethanol, cadmium, halothane and allyl alcohol,108 in causing hepatic injury.

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7. The role of LSECs in liver immunology 

7.1. LSECs and antigen processing 

LSECs are crucial to processing, scavenging, and tolerance induction responses to gastrointestinal antigens as well as circulating systemic antigens. LSECs constitutively express all molecules necessary for antigen presentation (CD40, CD54, CD80, CD86, MHC-I and MHC-II) and function as MHC-I and MHC-II restricted antigen-presenting cells (APC).27, 71, 74, 109 LSECs also exhibit antigenic resemblance to dendritic cells by expressing CD4, the mannose receptor, and CD 11C.110, 111, 112, 113 LSECs are very good antigen presenting cells and have been shown to induce proliferation, co-stimulation, and upregulation of cytokine production in CD4+ T cells.111, 114

7.2. LSECs and T cell interactions 

LSECs regulate the recruitment of specific lymphocyte subtypes. CD4 and CD8 T cells that simultaneously interact with LSECs have a tolerant phenotype.115 They suppress interferon-γ producing cells and promote IL-4-expressing helper T cell subset 2 (Th2) cells, creating immune suppression in the liver.116 LSEC primed CD4+ T cells differentiate into regulatory T cells, whereas myelocytic APC primed T cells differentiate into helper T cell subset 1 (Th1) cells.117 Therefore, LSEC primed CD4+ T cells play a crucial role in tolerance induction in the liver. The CD4+ T cell priming activity of LSECs can be negatively regulated by prostaglandin E2 (PGE2) and IL-10.111 LSECs also play a role in the development of tolerance by CD8 T cells towards orally administered antigens.118 LSECs are also important in tolerance induction in liver transplantation. In one study, the rejection of donor livers correlated closely with the presence of anti-LSEC antibodies, increased activation of T cells, and decreased transforming growth factor-β (TGF-β).21

7.3. LSECs and antigen scavenging 

In addition to antigen processing, LSECs scavenge antigens such as LPS and advanced glycation end-products.115, 119, 120, 121 Scavenging is distinctly different from antigen processing. LSECs endocytose glycoproteins, extracellular matrix components, immune complexes, transferrin, and ceruloplasmin, thereby clearing antigens from the vasculature.122

7.4. LSECs and immune surveillance 

LSECs may assist immune surveillance via T cell activation, which in turn is influenced by the milieu encompassing bacteria and LPS. LSECs express CD14, which serves as a receptor for the LPS binding protein.109, 123 LSECs also assist immune surveillance by releasing immunosuppressive mediators such as IL-10, PGE2, and TGF-β.21, 71, 111

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8. Pseudomonas aeruginosa infections and the liver 

8.1. Clinical impact of Pseudomonas aeruginosa infections 

P. aeruginosa is a common nosocomial bacterial pathogen associated with a high incidence of post-operative morbidity and mortality.124 Studies that describe P. aeruginosa as one of the most common multi-antibiotic resistant nosocomial organisms, especially in post-surgical and post-liver transplant scenarios, are shown in Table 2. Post-operative pseudomonal infections, including P. aeruginosa infections after liver transplantation,124, 125, 126 can result in sepsis,127, 128 bacteremia,125, 126 hepatic damage,129, 130 and fatal multiple-organ failure.127, 128

Table 2. Incidence of Pseudomonas aeruginosa in post-surgical and post-liver transplant infections
Study datesPatient cohortCohort sizePathogen parameter examinedCohort % with parameter presentIncidence of pseudomonal infectionsPathology specificsRef.
2000–2003Liver transplant30Bacteremia30%44% of bacteremia100% with bacteremia died174
1999–2003Liver transplant103Bacterial pneumonia32%17% of pneumonia50% with pneumonia had acute rejection175
1989–2003Liver transplant233Bacteremia52%Topmost 126
2001–2002Living donor liver transplant113Surgical site infection37%33% of Gram-negative bacterial infections26% with surgical site infection died125
1999–2002Liver transplant99Multiple antibiotic resistance57%23% of all bacterial infections63% of all infections by multi-antibiotic resistant bacteria124
1998–2001Liver transplant401Pneumonia5%>57% of pneumonia 176
1990– 1999Liver transplant165Multiple antibiotic resistance31%50% of multi-antibiotic resistant bacteriaHigher mortality177
1995–1998Liver transplant in ICU90Pulmonary infiltration40%27% of pneumonia38% with infiltrates had pneumonia178
1990– 1995Liver–lung–heart transplant in cystic fibrosis10Double organ transplants 100%100% multi- antibiotic resistant179
1990–1993Liver transplant284Aerobic Gram-negative bacteria45%Most frequently isolated from blood 180
1988–1991Liver transplant185Bacteremia and fungemia29%10% of bacteremia and fungemia95% of all infections nosocomial181
1985–1991Kidney transplant568Bacteremia and fungemia11%19% bacteremia and fungemia70% of all infections nosocomial181
1981–1984Liver transplant129Early death >24 h37%53% of deaths due to bacterial sepsisBacterial sepsis in 81% of deaths182

ICU, intensive care unit.

8.2. Pseudomonas aeruginosa toxins and the liver 

Pyocyanin, a redox-active, pro-inflammatory, pro-apoptotic, cytotoxic and immunomodulatory tricyclic phenazine metabolite is secreted in copious quantities by most P. aeruginosa strains. Though systemic, portal, or hepatic concentrations of pyocyanin have not been estimated in pseudomonal sepsis, it is well known that it is present in large amounts (up to 130μM) in respiratory secretions from cystic fibrosis and bronchiectasis patients with P. aeruginosa infections.131, 132, 133 Pyocyanin has been shown to exert its in vivo and in vitro cytotoxicity by impairing the cellular redox status and depleting intracellular GSH and thiols in endothelial cells,8 and in transformed epithelial cells134 via superoxide and H2O2 generation,8, 134 or through direct oxidation of GSH.134 Based on known effects by oxidants on the cellular cytoskeleton, pyocyanin-dependent increases in sinusoidal H2O2 could induce modifications in the cellular actin cytoskeleton leading to altered LSEC morphology.

The impact of LPS has already been discussed in earlier sections.

P. aeruginosa exotoxin A induces liver damage by protein synthesis inhibition, activation of KCs to produce TNF-α, and perforin-dependent, Fas-independent, apoptotic pathways.135 To induce substantial hepatocyte damage, P. aeruginosa exotoxin A requires the presence of T cells to stimulate KCs to secrete TNF-α.77, 135 For P. aeruginosa exotoxin A to synergize with LPS to induce severe hepatotoxicity, T cells are required to produce circulation of sustained high concentrations of TNF-α.78

8.3. LSECs and LPS 

When LSECs are incubated with LPS, specific immune responses by CD4+ cells are down-regulated.74 LPS also induces LSEC scavenger and endocytotic functions119 and subsequently antigen presentation to lymphocytes.111, 114 LPS can also induce sinusoidal thrombogenesis, fibrin degradation and deposition,99 as well as LSEC apoptosis via TNF secreted by KCs.136

LPS defenestrates LSECs.32 One intravenous dose of LPS (2mg/kg body weight stat) in Dark-Agouti rats reduced LSEC porosity significantly, the changes being spontaneously reversed after 14 days. With the same LPS dose, Sprague-Dawley rats showed similar but irreversible changes at least 3 days after LPS challenge.18 Intravenously injected LPS (2.5mg/kg body weight) in F344 rats resulted in LSEC enlargement, sieve plate disruption, and gap formation 6h after LPS challenge.19 KCs seem to modulate LPS-induced LSEC defenestration and impaired hyaluronan scavenging.137 Takei and co-workers reported that co-incubation of LSECs with LPS-stimulated KCs induced significant apoptosis in LSECs that come in contact with KCs. Anti-TNF-α antibody prevented the LPS-induced apoptosis.136

Alcohol abuse may promote the uptake of LPS from alcohol lysed gut bacteria or from direct injury to the intestinal wall.70 LPS could induce liver damage starting with the LSEC18 or secondary to KC and neutrophil70, 138 activation. This could be a pivotal pathogenic factor in alcoholic cirrhosis.

8.4. LSECs and pyocyanin 

Given the role of LSECs in liver allograft rejection21 and hyperlipidemia,22, 23 changes in the LSEC induced by pyocyanin may have significant clinical implications. As P. aeruginosa pyocyanin has been shown to deplete intracellular GSH and thiols in endothelial cells,8 the possibility that P. aeruginosa pyocyanin may impact LSEC structure and function by impairing the cellular redox status via generation of H2O2 and ROS and depletion of intracellular GSH and thiols was explored.

In our study exploring the effects of pyocyanin on isolated LSECs,20 we showed that pyocyanin treatment over a wide range of concentrations substantially reduced LSEC porosity. In our earlier study,16 we showed that catalase, which inactivates H2O2 to water, prevented pyocyanin-induced morphological changes including defenestration in the LSECs, suggesting a role for oxidative cellular injury in cellular pathogenesis of pyocyanin. However, in our study in intact in situ rat livers,20 portally injected pyocyanin (blood concentration of 12μM for 30min) induced a significant loss of porosity and a novel finding, endothelial thinning, without immunohistochemical evidence of changes in the well-characterized markers of oxidative change, malondialdehyde and 3-nitrotyrosine. As the latter in vivo findings appear to have the contradistinctive veneer to the former in vitro studies, it is plausible that in vivo, hepatocyte-derived antioxidants prevented overall changes in markers of oxidative stress, but the magnitude of the same was insufficient to prevent LSEC defenestration. Alternatively, it is possible that pyocyanin induces defenestration through mechanisms independent of oxidative stress. Using immunoblot binding-mobility and immunohistochemical techniques, we ruled out any role for caveolin-1, an important fenestration membrane protein that changes with fenestration changes.20 As pyocyanin has been shown to influence the expression and secretion of numerous cytokines,9, 139 further investigations into the expression and activity of these cytokines may serve to unravel the appropriate mechanisms. Our studies point to the LSECs as the initial site of pyocyanin-induced injury, and indicate the sentinel role of LSECs in protecting hepatocytes from endo- and xenobiotics.

In addition to a sentinel role for LSECs in hepatoprotectivity from bacterial toxins, there is a possibility that initial LSEC defenestration induced by P. aeruginosa pyocyanin and LPS may confer immune tolerance to circulating bacterial antigens and toxins, as it has been shown that early LSEC defenestration attenuates subsequent immune liver damage, pointing to LSEC defenestration as possibly a significant change in modifying hepatic immunological responses.76

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9. Hyperlipidemia of sepsis, bacteremia, and Gram-negative bacterial toxemia 

Sepsis is associated with free radical induction,140 altered redox balance,127, 128, 141 cellular NADH/ATP reduction,127 cellular cytoskeletal modifications, and decreased hepatic energy metabolism.127, 128, 142, 143 Strikingly similar changes can also be induced by Gram-negative bacterial toxins, either LPS88, 91, 144, 145, 146 or pyocyanin8, 12, 15, 134, 147, 148, 149, 150, 151, 152 alone. Conditions including the presence of free radicals and cytoskeletal modifying agents are particularly conducive to LSEC defenestration.

It is possible that LSEC defenestration induced by bacterial toxins such as LPS or pyocyanin may impede hepatic uptake of chylomicron remnants and increase their circulation time, leading to the hyperlipidemia of sepsis frequently reported in the literature.153, 154 Owing to this possibility, though it may not be immediately apparent that hyperlipidemia could be an index of altered lipoproteins from the portal system in clinical sepsis, the role of this mechanism may be as important, if not more important than the other possibilities elaborated below, including (1) suppression of peripheral lipoprotein lipase synthesis and activity, (2) enhanced catabolism of adipose tissue, and (3) increased hepatic lipoprotein turnover, modification, and egress. The currently accepted hypothesis for the pathogenesis of sepsis-associated hypertriglyceridemia posits that sepsis stimulates catecholamine release, which stimulates release of free fatty acids from adipose tissue, which are taken up by the liver, metabolized and then released as triglycerides in lipoproteins.142, 154 Alternatively, sepsis-stimulated TNF-α and IL-1 may suppress lipoprotein lipase synthesis, which decreases the rate of triglyceride clearance, leading to hypertriglyceridemia.142, 154 Both LPS injection and Escherichia coli bacteremia in rats result in hypertriglyceridemia and decreased lipoprotein lipase activity. Experimental sepsis stimulates liver putrescine and spermidine synthesis in addition to ornithine decarboxylase activation, responses that can also be simulated by LPS and pro-inflammatory cytokines.155 Therefore it is clear that not only sepsis, but also recurrent Gram-negative infections, bacteremia, and toxemia can lead to hypertriglyceridemia.

During endotoxemic states, one-third of LPS binds to high-density lipoproteins and is taken up into peripheral tissues. The remaining two-thirds are taken up more rapidly, predominantly in reticuloendothelial organs with abundant phagocytes, APCs, and cells with scavenger function.156, 157 Increased serum high-density lipoprotein and its LPS-binding capacity may serve to protect against LPS-induced damage in chronic alcohol exposure.158, 159

It has been shown that triglyceride-rich lipoproteins including very low density lipoproteins and chylomicrons are capable of binding LPS, forming lipoprotein–LPS complexes or chylomicron–LPS complexes.154 These complexes modulate the host immune responses and therefore impede LPS-induced toxicity. Chylomicron–LPS complexes inhibit nitric oxide release by hepatocytes much better than either of them alone, suggesting that chylomicron-bound LPS inhibits hepatocyte nuclear factor-kappa B (NF-κB) and prevents liver damage.160 Lipoproteins have also been shown to protect animals from lethal polymicrobial Gram-negative bacterial sepsis. Therefore it is possible that hypertriglyceridemia could be an innate immune response to Gram-negative sepsis.161 Alternatively, it could also be a possible mechanism to perpetuate LPS-induced toxicity owing to prolonged systemic LPS persistence.

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10. A morphopathogenetic mechanism for the hyperlipidemia of pseudomonal sepsis 

Pyocyanin significantly influences LSEC morphology and this fact may have substantial clinical implications. LSECs are crucial in tolerance induction in liver transplantation, and rejection of donor livers correlates closely with the presence of LSEC antibodies.21 Additionally, the LSEC responses to ischemia–reperfusion injury in the donor organ has been shown to alter the outcome of liver transplantation.162, 163 Following pseudomonal sepsis, damage to the LSEC induced by pyocyanin could impact the graft outcome and consequently the prognosis. As hyperlipidemia is an important response to sepsis and as the mechanism for sepsis-associated hyperlipidemia is multifactorial, impaired catabolism of lipoproteins is certainly a contributory factor.142, 154 LSECs, which are perforated with fenestrations that facilitate lipoprotein transfer between blood and hepatocytes, have been increasingly recognized to have a notable role in hyperlipidemia.22 Conditions associated with LSEC defenestration such as aging64 and treatment with the surfactant poloxamer 40753 are associated with impaired lipoprotein uptake by the liver and hypertriglyceridemia. Although it may not always be obvious that hyperlipidemia may be a reflection of altered lipoprotein removal from portal blood, the defenestration induced by pyocyanin supports the concept that sepsis-related hyperlipidemia might at least in part be a result of LSEC defenestration, alongside the other hypotheses described in section 9, including increased delivery of triglycerides from the liver, defective removal by peripheral tissues, and modified plasma lipoproteins. Pseudomonal sepsis with simultaneous release of toxins like pyocyanin and LPS, may lead to endothelial changes including loss of LSEC porosity, subsequently excluding lipoproteins from the liver, leading to lipoprotein retention in the peripheral circulation. This mechanism may be crucial in the contributory causality of sepsis-related hyperlipidemia (Figure 2).

  • View full-size image.
  • Figure 2. 

    Probable pathogenesis of pseudomonal sepsis-related hyperlipidemia. Liver sinusoidal endothelial cell (LSEC) defenestration in bacterial/pseudomonal sepsis owing to toxins like pyocyanin or endotoxin (lipopolysaccharide) may exclude lipoproteins from the liver leading to lipoprotein retention in the peripheral vasculature accounting for bacterial/pseudomonal sepsis-related hyperlipidemia.

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11. Therapeutic possibilities in Gram-negative bacterial sepsis 

LSEC fenestrations and liver sinusoidal porosity can be regulated with a variety of physiological and pharmacological agents (Table 1), as well as cytoskeletal manipulating agents (Table 3). Morphological changes in liver sinusoidal fenestrations have systemic implications particularly for lipoprotein metabolism,164 clearance of medications,23 and immunity,75 as well as conditional hepatoprotective effects.165

Table 3. Use of actin-disrupting agents to elucidate liver sinusoidal endothelial cell fenestration dynamics
Treatment agentPorosityFenestration diameterFenestration frequencyCytoskeletal changesOther changesRef.
1Antimycin A↓↓↓↓↓↓↑Actin disassembly↓ ATP+sieve plate protrusion43
2Cytochalasin B↑↑↑None, variable↑↑Actin disassembly+↑ polymerizationFFCs not connected to fenestrations37, 38, 183, 184
3Latrunculin A ↓↑↑Actin disassembly+↑ polymerizationFFCs not connected to fenestrations183, 184
4Misakinolide A ↓↑↑Actin disassembly+↑ polymerizationFFCs connected to fenestrations183, 185
5Swinholide A ↓↑↑Actin disassembly+↑ polymerizationFFCs not connected to fenestrations183, 185
6Jasplakinolide ↓↑Actin disassembly+F-actin bundle loss+↑ F-actin dotsFFCs not connected to fenestrations183, 185
7Hydrohalichondramide ↓↑↑Actin disassembly+↑ polymerizationFFCs not connected to fenestrations183, 186
8Dihydrohalichondramide ↓↑↑Actin disassembly+↑ polymerizationFFCs connected to fenestrations183, 186

ATP, adenosine triphosphate; FFC, fenestration forming center.

Endotoxemia alters Ca2+ homeostasis, with minute Ca2+ flux alterations.166 These changes, possibly due to catecholamine-mediated Ca2+ influx, are reversible by Ca2+ channel blockers.167 Under induced endotoxemia, Ca2+ channel blockers limit hepatocyte injury and inhibit LPS-induced KC inducible nitric oxide synthase expression.168 LPS-induced membrane fluidity of hepatocytes can be prevented by Ca2+ channel blockers.100 Ca2+ channel blockers curb the sepsis-induced acute phase response by preventing sepsis-related hepatic Ca2+ changes140 that lead to reorganization of fenestrations, and so modulate the metabolic response.

Pyocyanin or LPS trigger oxidant stress. This could lead to an increased sinusoidal efflux of GSH and its extracellular oxidation. GSH is depleted in LPS-mediated hepatic injury.88 Animal models have shown that antioxidants such as GSH169 and adequate nutrition170 are protective in septic shock. Superoxide generation in the hepatic sinusoid in response to LPS challenge is likely to be a factor involved in liver damage.91 Superoxide dismutase, which dismutates superoxide to H2O2 has been shown to offer protection against LPS-induced liver injury.140

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Acknowledgements 

We thank Prof. Robin Fraser, Department of Pathology, Christchurch School of Medicine, University of Otago, Christchurch, New Zealand, for his continued mentorship and assistance.

Conflict of interest: No conflict of interest to declare.

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PII: S1201-9712(10)02398-2

doi:10.1016/j.ijid.2010.02.2263

International Journal of Infectious Diseases
Volume 14, Issue 10 , Pages e857-e867, October 2010

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