Prevention of Gram-Negative Translocation Reduces the
Severity of Hepatopulmonary Syndrome

Anne Rabiller, Hilario Nunes, Didier Lebrec, Khalid A. Tazi, Myriam Wartski, Elisabeth Dulmet, Jean-Marie Libert,
Christine Mougeot, Richard Moreau, Michel Mazmanian, Marc Humbert, and Philippe Hervé

Laboratoire de Chirurgie Expérimentale-UPRES, Centre Chirurgical Marie Lannelongue, Université Paris Sud, Paris; and Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U-481, Hôpital Beaujon, Clichy, France Hepatopulmonary syndrome (HPS) is characterized by intrapulmo-
bly cause macrophage sequestration by inducing coordinated nary vascular dilatations and an increased alveoloarterial oxygen dif-
expression of macrophage and endothelium adhesion mole- ference (AaPO2). These abnormalities are related to augmented
cules, as well as local release of monocyte chemotactic factors pulmonary nitric oxide (NO) production, dependent primarily on
(7, 8). During phagocytosis, activated macrophages release increases in the expression and activity of inducible NO-synthase
numerous secretory products into the extracellular environ- (iNOS) within pulmonary intravascular macrophages and, to a lesser
ment, including cytokines and nitric oxide (NO) (7, 8). Our extent, of endothelial NOS (eNOS). Production of iNOS by pulmo-
finding in a recent study (6) that inducible NO-synthase (iNOS) nary intravascular macrophages might be related to translocated
was expressed in the pulmonary intravascular macrophages of gut bacteria present in the pulmonary circulation. To test this hy-
cirrhotic rats may explain the increase in lung production of pothesis, we determined whether macrophage sequestration, lung
NO in this animal model (6). Rats with cirrhosis induced by iNOS expression and activity, and HPS severity were decreased af-
common bile duct ligation (CBDL) (6, 9, 10) develop hepato- ter norfloxacin was given for 5 weeks to prevent Gram-negative
pulmonary syndrome (HPS) with intrapulmonary vascular di- bacterial translocation in rats with common bile duct ligation-
induced cirrhosis. Norfloxacin decreased the incidence of Gram-

latations, an increased alveoloarterial oxygen difference (AaPO2), negative translocation from 70 to 0% and the percentage of pul-
and a hyperdynamic state replicating the abnormalities seen in monary microvessels containing more than 10 macrophages from
human HPS (11). This syndrome has been shown to result in large 52 Ϯ 7 to 21 Ϯ 8% (p Ͻ 0.01). AaPO
part from overproduction of NO in the lung: giving N(G)-nitro- 2 and cerebral uptake of intra-
venous 99mTc-labeled albumin macroaggregates (reflecting intra-
L-arginine methyl ester to normalize lung NO production pre- pulmonary vascular dilatations) were intermediate to those of
vented HPS in cirrhotic rats (6). Taken together, these find- untreated cirrhotic and sham-operated rats. The activity and ex-
ings suggest that translocation of gut bacteria in cirrhotic rats pression of lung iNOS, but not eNOS, were reduced to normal.
may be an important step in the pathogenesis of HPS.
Norfloxacin may reduce HPS severity by inhibiting Gram-negative
Norfloxacin, a quinolone predominantly active against Gram- bacterial translocation, thereby decreasing NO production by pul-
negative bacteria, has been shown to prevent bacterial translo- monary intravascular macrophages. Bacterial translocation may be
cation in cirrhotic patients (12, 13). The aim of the present the key to the pathogenesis of HPS.
study was to determine whether giving prophylactic norfloxa-cin treatment to rats with CBDL would decrease pulmonary Keywords: experimental cirrhosis; hepatopulmonary syndrome; mac-
intravascular macrophages and lung iNOS expression and ac- rophage; bacterial translocation; nitric oxide synthase In cirrhosis, intestinal bacterial overgrowth, impaired host de-fenses, and disruption of the gut mucosal barrier may promote bacterial translocation, i.e., dissemination of gut lumen bacte- ria within the body (1-3). Bacterial translocation has been The study protocol was reviewed and approved by the institutional found in 45-75% of animals with experimental cirrhosis (1-3).
animal care committee. Male Wistar rats were subjected to CBDL as Normally, the lung vascular bed is not exposed to large previously described (14). Four groups of 20 rats were studied 5 weeks amounts of bacterial products: these are filtered out by the after CBDL or a sham operation: a norfloxacin-treated CBDL group, liver, whose Kupffer cells clear nearly all gut bacteria and bac- an untreated CBDL group, a norfloxacin-treated sham-operated group, terial endotoxins from the bloodstream (4). In cirrhosis, the and an untreated sham-operated group. Norfloxacin was given by development of portosystemic shunts and the dramatic de- gavage after surgery for 5 weeks in a dose of 10 mg kg 1 day 1.
crease in the phagocytic capacity of the liver allow circulating Hemodynamic and Blood Gas Measurements
bacteria or bacterial endotoxins to enter the pulmonary circu- lation. In this situation, the lungs clear the blood of gut bacte- After anesthesia using intraperitoneal ketamine (100 mg kg ) and ria and endotoxins (3, 4), thereby compensating for the de- xylazine (0.75 mg kg ), the rats were ventilated with room airthrough a tracheotomy. Catheters were inserted into the pulmonary crease in liver phagocytic function (4). This increase in and the tail arteries. A thermistor was positioned in the aortic arch to pulmonary phagocytic activity is ascribable to extensive accu- measure cardiac output. AaPO was calculated using the modified al- mulation of pulmonary intravascular macrophages that ad- veolar gas equation. Hemodynamic and blood gas values were re- here to the pulmonary endothelium (4-6). Pathogens that are corded 30 minutes after the ventilation was adjusted to obtain an arte- translocated from the gut to the pulmonary circulation proba- rial carbon dioxide pressure between 35 and 45 mm Hg. At the end ofthe hemodynamic study, a laparotomy was performed to measureportal pressure, to sample blood from the inferior vena cava for aspar-ate aminotransferase (ASAT) and aspartate alanine transferase (ALAT) (Received in original form January 15, 2002; accepted in final form May 3, 2002) measurements, and to remove and weigh the spleen and liver.
Correspondence and requests for reprints should be addressed to P. Hervé, M.D.,Centre Chirurgical Marie Lannelongue, 133 avenue de la Résistance, 92350 Le Detection of Intrapulmonary Vascular Dilatations
Plessis Robinson, France. E-mail: pherve@ccml.com Am J Respir Crit Care Med
Vol 166. pp 514-517, 2002
Thirty minutes after the injection of 200 ␮Ci of DOI: 10.1164/rccm.200201-027OC
macroaggregates into the jugular vein, the ratio of brain-over-lung ra- Internet address: www.atsjournals.org
Rabiller, Nunes, Lebrec, et al.: Translocation in Hepatopulmonary Syndrome Bacteriology Studies
like cells within the lumen of numerous small muscular and The rats were anesthetized, and the abdominal skin was shaved and nonmuscular pulmonary vessels. The percentages of vessels sterilized with an iodine solution. A swab of ascitic fluid from the peri- with more than 10 adherent macrophages was 52 Ϯ 7% in the toneal cavity was plated onto chocolate agar plates. Three milliliters untreated CBDL group but only 21 Ϯ 8% in the norfloxacin- of blood was withdrawn from the inferior vena cava and inoculated into aerobic and anaerobic Bactec culture bottles. The mesentericlymph nodes were dissected and plated onto chocolate agar plates.
Any positive mesenteric lymph node cultures were considered indica- Culture-positive mesenteric lymph nodes, indicating that trans- tive of bacterial translocation from the intestinal lumen.
location had occurred, were found in 67% of norfloxacin- Lung NOS Activity Measurements
treated CBDL rats and 70% of untreated CBDL rats. Bacte-rial peritonitis occurred in 25% of untreated CBDL rats and Total and calcium-independent NOS activities were measured in lung 50% of norfloxacin-treated CBDL rats. Blood cultures were homogenates by determining the conversion of [14C]L-arginine to[14C] positive in 40% of norfloxacin-treated and untreated CBDL L-citrulline as previously reported (15-18).
rats. Thus, the overall incidences of positive cultures were sim- Lung NOS Protein Expression
ilar in the norfloxacin-treated and untreated CBDL animals.
Expression of endothelial NOS (eNOS) and iNOS protein in the lungs However, the organisms recovered from the cultures were very was determined using specific antisera against eNOS and iNOS (Trans- different between these two groups. Gram-positive bacteria duction Laboratories, Lexington, UK) (15-18). Densitometry results were found in 100% of culture-positive specimens of mesen- are expressed as percentages of the value in untreated control animals teric lymph nodes, ascites, and blood from the norfloxacin- treated animals, compared with 60% (p ϭ 0.07), 50% (p ϭ0.04), and 0% (p Ͻ 0.0001), respectively, in the untreated CBDL Microscopic Examination
rats. Isolated bacteria in untreated CBDL rats' mesenteric Distended lungs (four rats in each group) were fixed by infusion of lymph nodes included Enteroccus faecalis, Escherichia coli, 10% formalin at a pressure of 25 cm H2O into the trachea. Lung sec- Bacillaceae, and Klebsiella pneumoniae. Isolated bacteria in tions (4 ␮m) were stained with hematoxylin and eosin. We (6) and norfloxacin-treated CBDL rats mesenteric lymph nodes in- others (4) have recently shown that small pulmonary vessels of cir- cluded E. faecalis, Streptococcus, Staphylococcus, and Coryne- rhotic rats had adherent large mononuclear macrophage-like cells bacterium species. No bacterial growth occurred in any of the strongly immunoreactive for the specific rat macrophage monoclonalantibody ED1. To quantify intravascular macrophage sequestration, specimens of mesenteric lymph nodes, ascites, or blood from 60 vessels per animal were examined and the percentage of vessels with more than 10 mononuclear macrophage-type cells was deter-mined in each group. Only vessels that were circular in cross section Pulmonary Hemodynamics
Untreated CBDL rats exhibited a characteristic hemodynamicpattern of pulmonary and systemic arterial vasodilation with Statistical Analysis
hyperdynamic circulation, as indicated by lower pulmonary Results were evaluated using analysis of variance followed by Fisher's and systemic vascular resistance values and higher cardiac in- post hoc tests. Because results were similar in the norfloxacin-treated dex values as compared with the other groups (Table 1). Nor- and untreated sham-operated groups, these were combined for subse- floxacin-treated CBDL rats had total pulmonary vascular re- quent analysis. All values are reported as means Ϯ SEM. The p values sistance values and cardiac index values intermediate to those of less than 0.05 were considered statistically significant.
in the untreated CBDL animals and in the sham-operated ani-mals (Table 1).
All rats subjected to CBDL became jaundiced, and most had Hepatopulmonary Syndrome in Cirrhotic Rats
ascites and a micronodular liver. Gross and histologic findings Assessment of HPS in the CBDL rats was based on the combi- at autopsy confirmed that all CBDL rats had cirrhosis. ASAT nation of gas exchange abnormalities and intrapulmonary vas- and ALAT blood concentrations, liver and spleen weights, cular dilatations. Arterial carbon dioxide pressure was similar and portal venous pressure levels were similar in the norfloxa- in all groups. In the untreated CBDL rats, AaPO2 and the ratio cin-treated and untreated CBDL groups. All these values were of brain-over-lung radioactivity were substantially higher than significantly higher than in the sham-operated animals. Post- in the sham-operated animals, reflecting the presence of intra- operative mortality was less than 1%. Five-week mortality rates pulmonary vascular dilatations (Table 1). In norfloxacin- were similar in the two groups of CBDL rats (25% with and treated CBDL rats, AaPO2 and brain-over-lung radioactivity ratio were intermediate to those in the untreated CBDL rats All lungs from norfloxacin-treated and untreated CBDL and in the sham-operated rats, indicating less severe HPS than rats showed accumulation of large mononuclear macrophage- in the untreated CBDL rats (Table 1).
Cardiac index, ml minϪ1 (100 g body wt)Ϫ1 Total pulmonary vascular resistance, mm Hg mlϪ1 minϪ1 (100 g body wt)Ϫ1 Definition of abbreviations: CBDL ϭ common bile duct-ligation.
* Results are means Ϯ SEM.
† Significantly different from untreated rats with CBDL (p Ͻ 0.05).
‡ Significantly different from sham rats (p Ͻ 0.05).
Figure 2. Protein expres-
Total and calcium-independent NOS activities in the lungs were sion of eNOS in lung ho-mogenates from untreated 2.8- and 3.9-fold higher, respectively, in untreated CBDL rats as compared with sham-operated rats (Figure 1). As com- pared with untreated CBDL rats, total lung NOS activity was 18% lower and calcium-independent NOS activity 41% lower (p Ͻ 0.01) in the norfloxacin-treated CBDL rats. Levels of cal- cium-independent NOS activities were similar in norfloxacin- each group, and bar de-picting eNOS protein con- treated CBDL and sham-operated animals. Total and cal- cium-independent lung NOS activities were correlated with each other in the two CBDL groups, indicating that variations in calcium-independent NOS activity accounted for most of means Ϯ SEM of the percentage increase from sham eNOS values. *Sig- the change in total NOS activities (r ϭ 0.89, p ϭ 0.01).
nificantly different from sham rats (p Ͻ 0.05).
Lung NOS Expression
Levels of eNOS protein expression in the lungs increased sim- microcirculation accounts for this shift in phagocytosis from ilarly in norfloxacin-treated and untreated CBDL rats as com- the liver to the lung. Miot-Noirault and coworkers (4) and pared with sham-operated animals (142 Ϯ 10 and 122 Ϯ 7% of Chang and colleagues (5) have demonstrated that these pul- sham values, respectively; p Ͻ 0.01) (Figures 2 and 3). As com- monary intravacular macrophages derive from circulating pared with sham-operated animals, iNOS protein expression monocytes, not from emigrating Kupffer cells. In the present was higher in the lungs of untreated CBDL rats (260 Ϯ 10% of study, norfloxacin decreased the number of intravascular mac- sham-operated values, p Ͻ 0.01). In contrast, no significant rophages adherent to the pulmonary microvessel endothe- difference was found in norfloxacin-treated CBDL rats (37 Ϯ lium. This cannot be ascribed to a lower incidence of bactere- mia, as bacteremia occurred in similar proportions of animalsin the two groups. The most likely explanation is a decrease in DISCUSSION
adhesion molecule expression (19) and/or in proinflammatorycytokine release (20) upon stimulation of macrophages and The goal of the present experimental study on the role of bac- endothelial cells by Gram-positive bacteria, as compared with terial translocation in the pathogenesis of HPS was to deter- mine whether prophylactic norfloxacin treatment prevents HPS In an earlier study of cirrhotic rats, we found an increase in in rats with cirrhosis. Norfloxacin decreased the incidence of pulmonary NO production related to increased expression Gram-negative, but not Gram-positive, bacterial transloca- and activity of pulmonary intravascular macrophage iNOS and, tion, the number of macrophages sequestered in pulmonary to a lesser extent, of lung eNOS (6). Norfloxacin markedly re- microvessels, the expression and activity of lung iNOS, and duced iNOS expression and activity in the lungs of these cir- rhotic animals. This was probably ascribable to both a de- As previously reported in human and experimental cirrho- crease in the number of pulmonary intravascular macrophages sis (1, 2, 12, 13), the incidence of bacterial translocation, i.e., and a lower level of induction of macrophagic NOS by Gram- extraintestinal dissemination of gut bacteria, was high in our rats with CBDL-induced cirrhosis: about 70% had positive Norfloxacin treatment decreased the severity of HPS in the mesenteric lymph node cultures. Norfloxacin did not reduce CBDL rats, as indicated by the intermediate AaPO2 and brain- the incidence of bacterial translocation to mesenteric lymph over-lung radioactivity values between those in sham-operated nodes, and it did not decrease the incidence of peritoneal in- and in untreated CBDL rats. Pulmonary vascular resistance fection or bacteremia. However, norfloxacin selected Gram- values were also halfway between those in the sham-operated positive pathogens: all bacteria recovered from blood speci- and untreated CBDL rats. We suggest that the decrease in NO mens were Gram-positive in the norfloxacin-treated group and release by the pulmonary intravascular macrophages may ac- Gram-negative in the untreated group. Similar selection of count for these results. Support for this hypothesis comes from Gram-positive flora has been reported with norfloxacin pro- our previous findings (6) that the magnitude of intrapulmo- phylaxis in humans and rats with cirrhosis (2, 13).
nary shunting (as an index of intrapulmonary vascular dilata- Although we did not investigate whether the pulmonary in- tion) correlated with the level of pulmonary NO production travascular macrophages of our cirrhotic rats contained bacte- and that inhibition with N(G)-nitro-L-arginine methyl ester of ria, a recent study indicates that the lung becomes the main pulmonary iNOS- and eNOS-derived NO production prevented site of clearance of bacteria and endotoxins in cirrhotic rats(4), thus compensating for the decrease in liver Kupffer cellactivity (4). Accumulation of macrophages in the pulmonary Figure 3. Protein expression
of iNOS in lung homoge-
nates from untreated cir-
rhotic rats, norfloxacin-
Figure 1. Total and calcium-
as means Ϯ SEM of the percentage increase from sham iNOS values.
*Significantly different from sham rats (p Ͻ 0.05).
Rabiller, Nunes, Lebrec, et al.: Translocation in Hepatopulmonary Syndrome HPS and pulmonary vasodilatation (6). Prevention of HPS and travascular phagocytosis and endotoxin sensitivity in rats. J Clin Invest pulmonary vasodilation was incomplete with norfloxacin. This may be ascribable to the persistent increase in lung eNOS- 6. Nunes H, Lebrec D, Mazmanian M, Capron F, Heller J, Tazi KA, Zer- bib E, Dulmet E, Moreau R, Dinh-Xuan AT, et al. Role of nitric oxide derived NO production in the norfloxacin-treated CBDL rats.
in hepatopulmonary syndrome in cirrhotic rats. Am J Respir Crit Care Several studies (1, 22) have demonstrated that eNOS upregula- tion was a consequence of the increased shear stress caused by 7. Panos RJ, Backer SK. Mediators, cytokines, and growth factors in liver- hyperdynamic circulation. Thus, the increases in lung eNOS ex- lung interactions. Clin Chest Med 1996;17:151-169.
pression and activity might be related to the persistent increase 8. Mantovani A, Muzio M, Garlanda C, Sozzani S, Allavena P. Macro- in cardiac index in the norfloxacin-treated CBDL animals.
phage control of inflammation: negative pathways of regulation of in-flammatory cytokines. Novartis Found Symp 2001;234:120-131.
Factors other than iNOS inhibition may be involved also.
9. Chang SW, Ohara N. Pulmonary circulatory dysfunction in rats with bil- One hypothesis is that norfloxacin administration may influ- iary cirrhosis: an animal model of the hepatopulmonary syndrome.
ence the development of portal hypertension and the natural Am Rev Respir Dis 1992;145:796-805.
history of obstructive hepatic injury, thus altering the produc- 10. Fallon MB, Abrams GA, McGrath JW, Hou Z, Luo B. Common bile tion and/or metabolism of other mediators by the liver. This duct ligation in the rat: a model of intrapulmonary vasodilatation and hypothesis is ruled out, however, by the similar severity of he- hepatopulmonary syndrome. Am J Physiol 1997;272:G779-G784.
11. Hervé P, Lebrec D, Brenot F, Simonneau G, Humbert M, Sitbon O, patic injury and portal hypertension in the two CBDL groups.
Duroux P. Pulmonary vascular disorders in portal hypertension. Eur Our study has important implications. It supports the useful- Respir J 1998;11:1153-1166.
ness of selective intestinal decontamination with norfloxacin 12. Gines P, Rimola A, Planas R, Vargas V, Marco F, Almela M, Forne M, previously suggested by prospective studies in which norfloxa- Miranda ML, Llach J, Salmeron JM, et al. Norfloxacin prevents spon- cin therapy reduced the risk of extra-peritoneal infections in taneous bacterial peritonitis recurrence in cirrhosis: results of a dou- patients with cirrhosis (12, 13). Another potential beneficial ble-blind, placebo-control trial. Hepatology 1990;12:716-724.
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Acknowledgment : The authors thank Odile Poirel for her excellent techni-
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