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Cavriani, Gabriela*; Domingos, Helori Vanni*; Soares, Alexandre Learth*; Trezena, Aryene Goes; Ligeiro-Oliveira, Ana Paula*; Oliveira-Filho, Ricardo Martins*; Sudo-Hayashi, Lia Siguemi*; Tavares de Lima, Wothan*

Basic Science Aspects

We investigated in rats the influence of the lymphatic system and of tumor necrosis factor (TNF) on the lung inflammation resulting from intestinal ischemia/reperfusion (I/R) performed by 45-min occlusion of the superior mesenteric artery followed by 2 h of reperfusion. A group of rats had the thoracic lymph duct ligated before I/R. In lungs, intestinal I/R evoked a significant neutrophil recruitment, and enhanced microvascular permeability, in addition to generation of TNF in serum. In the gut, there was lowered lactate dehydrogenase (LDH) activity and increased microvascular permeability. Upon lymph duct ligation, I/R rats had a significant reduction of pulmonary neutrophil recruitment and plasma extravasation, in addition to high amounts of TNF in the lymph, contrasting with undetectable levels in the serum. In addition, LDH gut levels in these animals were close to basal values; there was also some (yet significant) reduction of microvascular permeability, suggesting that the ligation of the lymphatic duct exerted some degree of protection against the intestinal injury caused by I/R. In I/R rats, the treatment with pentoxifylline (PTX) reduced TNF in serum and blunted other lung alterations. The gut alterations caused by intestinal I/R were largely blocked by PTX. On the other hand, in I/R rats with lymph duct ligation, PTX exacerbated the reduction of pulmonary neutrophil recruitment, but did not affect pulmonary and intestinal microvascular permeabilities. Similarly, intestinal LDH activity and serum TNF levels were unaffected. Overall, our data show that the pulmonary and gut injuries induced by intestinal I/R are partially dependent on TNF, which is conceivably generated in the injured gut tissue due to intestinal I/R and carried by the lymphatic system. Thus, the mesenteric lymphatic drainage seems to play a role as a path modulator of the pulmonary and intestinal dysfunctions that follow a gut trauma.

*Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brasil, and Laboratory of Anaerobic Vaccines, Institute Butantan, São Paulo, Brasil

Received 18 Nov 2004;

Address reprint requests to Dr. Wothan Tavares de Lima, Av. Prof. Lineu Prestes, 1524, Cidade Universitaria, 05508-900 Sao Paulo (SP), Brazil. E-mail:

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Abdominal trauma associated with intestinal ischemia/reperfusion (I/R) may affect distal organs, particularly the lungs (1, 2). Intestinal I/R is also associated with a systemic inflammatory response, suggesting a causal link between injury-released mediators and the pulmonary dysfunction of adult respiratory distress syndrome (ARDS) (3). Experimental models and clinical findings indicate that the lung injuries and the increased microvascular leakage of ARDS result from enhanced endothelium-neutrophil interactions (4). Interestingly, it has been demonstrated that neutrophil adhesion to endothelium is a rate-limiting step in the pathogenesis of lung injury after intestinal I/R (5). However, the ARDS-related mechanisms accounting for the pulmonary neutrophil accumulation and increased microvascular permeability seen after an abdominal trauma are still unclear.

Models of hemorrhagic trauma and septic shock in rodents have shown that the injured gastrointestinal tract is a potential source of inflammatory mediators that may eventually lead to the pulmonary dysfunctions observed in ARDS (6). In this context, the lymphatic system might constitute a path for such inflammatory mediators generated in the injured gut to approach the pulmonary microcirculation (7). In fact, an increased expression of ICAM-1 was reported in isolated neutrophils stimulated with samples of mesenteric lymph from posthemorrhagic rats (8). In this context, ligation of the mesenteric lymphatic duct of rats exposed to shock significantly reduced the leukosequestration in the lungs (9). Notwithstanding, organs other than the gut may contribute as sources of inflammatory cytokines (10).

Tumor necrosis factor (TNF), a proinflammatory cytokine with a wide spectrum of activities, is involved in the circulatory shock, in sepsis, and in multiple organ failure (11). In addition, TNF plays a pivotal role in local and remote inflammatory responses evoked by intestinal I/R (12, 13). In lungs, for example, TNF causes mechanical dysfunction (14) and increases microvascular permeability (15, 16). Furthermore, TNF also induces the release of neutrophil proteases and causes an increased respiratory burst. Taking into account that TNF is central for the genesis of local and systemic inflammation after intestinal I/R, the understanding of the mechanisms accounting for its transport is of interest.

In this study, the putative role of the lymphatic system as a TNF carrier was investigated in a model of pulmonary and systemic inflammation caused by intestinal I/R.

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Male, 180- to 200-g Wistar rats from our Departmental facilities were used. The animals were housed in controlled-temperature (21-23°C) and controlled-light (12-h light/12-h dark cycle; lights on 7:00 a.m.) conditions, and were given free access to food and water. Animals were housed and used in accordance with the guidelines of the Committee on Care and Use of Laboratory Animal Resources of the Institute of Biomedical Sciences, University of São Paulo (these guidelines are similar to those of the Canadian Council on Animal Care and the NIH Institutional Animal Care and Use Committee Guidebook).

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Intestinal I/R rat model

Laparotomy was done under anesthesia with ketamine (100 mg/kg, i.p.) and xylazine (20 mg/kg, i.p.). In the ischemic group of rats, a microsurgical clip (Vascu-statt® no 1001-531; Scalan International, St. Paul, MN) was applied to occlude the superior mesenteric artery. After a 45-min occlusion, the clip was removed and intestinal perfusion was re-established. The animals were killed 2 h later by exsanguination, via the abdominal aorta, under deep anesthesia. A sham operation was performed in the control group of rats. An additional group of nonmanipulated rats was added to obtain normal values of the variables studied.

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Thoracic lymphatic duct ligation

Upon a midline laparotomy, the lymphatic thoracic duct was identified as the narrowed duct extension of the cysterna chili (17). Thereafter, the thoracic lymphatic duct was dissected and the ligation procedure was performed as described elsewhere (18).

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Collection of lymph

The thoracic lymphatic duct was cannulated using a heparinized (50 UI) sylastic tubing (0.6 mm inner and 1 mm outer diameter). The cannula was tied in the thoracic lymphatic duct and the rats were subjected to intestinal I/R, as described above. The surgical incision was sutured and the animals were placed in Bollman-type restraining cages, with lymph being continuously collected (18). The thoracic lymph was collected 15 min before the induction of intestinal ischemia, during the ischemia period (45 min), and during the reperfusion period (2 h). The collected lymph was centrifuged at 170 g for 10 min and was stored at -80°C until further determinations.

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Lung myeloperoxidase (MPO) activity

MPO was measured as an index of the presence of neutrophils. Lung tissue samples were obtained from rats killed after intestinal reperfusion (n = 10). The lungs were perfused via the pulmonary artery with pH 7.0 phosphate-buffered saline (PBS) containing 5 IU/mL heparin (19). Samples were prepared as described elsewhere (20, 21). Briefly, to normalize the pulmonary MPO activity among the groups, whole lung was homogenized with 3 mL/g PBS containing 0.5% of hexadecyl-trimethylammonium bromide and 5 mM EDTA, pH 6.0. The homogenized samples were sonicated (Vibra Cell®, Sonics Materials, Newtown, CT) for 1 min and were then centrifuged at 37,000 g for 15 min. Samples of lung homogenates (20 μL) were incubated for 15 min with H2O2 and ortodianisidine; the reaction was stopped by the addition of 1% NaN3. Absorbance was determined at 460 nm using a microplate reader (Bio-Tek Instruments, Winooski, VT). Lung MPO activity was also measured in sham-operated (n = 10) and nonmanipulated rats (n = 5).

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Pulmonary and intestinal microvascular leakage

Lung and intestinal vascular permeability were assessed in the same rats using the Evans blue (EB) dye extravasation procedure (22). Briefly, rats subjected (n = 10) or not (n = 10) to intestinal I/R were injected with EB dye (Sigma, St. Louis, MO; 20 mg/kg, i.v.) 15 min before being killed. At selected times, the rats were killed, the lungs were perfused as described above, and two samples of lung parenchyma were taken. In a parallel series of experiments, fragments of ileum were also collected. The lumen of intestine was perfused with 10 mL of PBS and was then dissected free from adherent tissue. All of the samples of pulmonary and intestinal tissues were weighed; one fragment of every tissue was incubated in formamide (4 mL/g wet weight) at room temperature for 24 h. The other fragments were put to dry in an oven at 60°C and the corresponding dry/wet tissue weight ratios were then calculated as an index of edema. The concentration of EB dye extracted to formamide was determined spectrophotometrically at 620 nm (Bio-Tek Instruments) using a standard curve of the dye (0.3-100 μg/mL in formamide). EB extravased was expressed as micrograms per gram of dry tissue weight, thus avoiding the changes to be underestimated due to eventual edema formation.

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Quantification of TNF activity

TNF activity was quantified in serum and lymph using a cytotoxicity assay (L-929 lineage cells) according to Flick and Gifford (23). After intestinal reperfusion (n = 10), samples of blood from abdominal aorta and lymph from thoracic lymphatic duct were centrifuged at 170 g during 10 min. The cell-free lymph and sera were then stored at -80°C until further analyses. TNF activity was assayed in 50-μL samples, serially diluted (2-fold dilutions) in 96-well plates harvested with L-929 cells (2.5 × 104 cells/well), in the presence of actinomycin D (final concentration 5 μg/mL, AMRESCO®). After overnight incubation, the degree of cell lysis was assessed by staining with a 0.05% crystal violet solution in 10% methanol for 15 min, followed by rinsing the plates with distilled water and drying. Methanol (10%) was then added to each well to dissolve the stain and the absorbance was read at 620 nm on a microplate reader (Bio-Tek Instruments). The TNF titer (units per milliliter) was defined as the reciprocal of the dilution that induces 50% of lysis of L-929 cells.

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Measurement of lactate dehydrogenase (LDH)

LDH activity in intestinal tissues, was measured according Takada et al. (24). Tissue damage causes release of LDH into the lumen of injured intestinal tissues, therefore decreasing its content in the intestinal tissue. Accordingly, LDH activity was measured as an inverse marker of the intestinal injury caused by intestinal I/R (n = 10). Briefly, intestinal tissues (100-200 mg) from intact (n = 10) and ligated duct rats (n = 10) subjected to intestinal I/R were homogenized in 5 mmol/L of phosphate buffer, pH 7.4, and centrifuged (at 12,000 g for 15 min at 4°C). Basal values were obtained using a non manipulated group of rats (n = 5). LDH activity was determined from the supernatants using a commercially available kit (Labtest Diagnostica, Belo Horizonte, Brazil) and expressed as units per milligram of tissue wet weight. Absorbance was read at 340 nm on a microplate reader spectrophotometrically (Bio-Tek Instruments).

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PTX treatment

Sixty minutes before intestinal I/R, groups of intact rats (n = 10) and those subjected to thoracic lymphatic duct ligation (n = 10) were treated by gavage with 120 mg/kg PTX (Trental®). This protocol was chosen by following Kotadia et al. (25), who showed that this dose of PTX prevented the suppressive effects of thermal injury on the activity and the IL-2 production by mesenteric lymph node T cells.

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Statistical analysis

Data are expressed as mean ± SEM. Differences were compared using analysis of variance, followed by Student-Newman-Keuls post hoc analysis. Values of P < 0.05 were considered to be statistically significant.

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Pulmonary MPO activity

Figure 1 shows that the increased pulmonary MPO activity (O.D., 0.532 ± 0.020) of rats with intact thoracic lymphatic duct and subjected to the intestinal I/R (intact duct) was significantly reduced (O.D., 0.331 ± 0.02) after ligation of thoracic duct (ligated duct). Pulmonary MPO activity was also significantly increased in sham-operated rats with a ligated duct (O.D., 0.140 ± 0.010) as compared with sham-operated rats (O.D., 0.079 ± 0.013) and with basal values (O.D., 0.055 ± 0.005).

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EB extravasation

Figure 2 shows the magnitude of the increase of the pulmonary microvascular permeability of rats after intestinal I/R in the presence (intact duct) and absence (ligated duct) of normal lymphatic flow. It is seen that the occlusion of the lymphatic duct after intestinal I/R decreased significantly the extravasation of EB dye (66.4 ± 5.1 μg EB/g dry weight) as compared with values after intestinal I/R in rats with an intact lymphatic flow (109.4 ± 7.5 μg EB/g dry weight). Finally, the pulmonary microvascular permeability did not vary in sham-operated rats of both groups of rats (with an intact and ligated duct) as compared with the basal value (53.6 ± 10.8 μg EB/g dry weight).

Figure 3 shows that rats subjected to intestinal I/R with an occluded thoracic lymphatic duct had a significantly reduced intestinal EB dye extravasation (165.8 ± 19.4 μg EB/g dry weight) as compared with its extravasation with intact thoracic lymphatic duct (238.1 ± 33.0 μg EB/g dry weight). The amount of EB dye extravased in the intestine of sham-operated rats with occlusion of lymphatic duct was significantly increased (92.3 ± 1.6 μg EB/g dry weight) as compared with that of sham-operated rats with intact thoracic lymphatic duct (57.0 ± 6.2 μg EB/g dry weight) and was not different from that of the basal group (89.9 ± 9.5 μg EB/g dry weight).

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Figure 4 shows that the levels of TNF in the sera of rats subjected to intestinal I/R with an intact thoracic lymphatic duct were elevated (33.5 ± 5.3 U/mL) relative to the sham-operated animals (16.3 ± 2.7 U/mL). Those levels were drastically reduced when intestinal I/R was induced in rats with an occluded lymphatic duct (0.82 ± 0.45 U/mL). Sham-operated rats of both groups (intact and ligated) did not show differences in serum TNF levels. However, these values were significantly higher than those found in the basal group (basal, 0.10 ± 0.001 U/mL; intact, 16.3 ± 2.7 U/mL; ligated, 18.0 ± 4.0 U/mL).

The TNF contents in lymph collected during the experiment are shown in Figure 5. The levels were significantly increased at reperfusion (31.9 ± 6.5 U/mL) relative to those found during ischemia (1.7 ± 0.2 U/mL) or 15 min before the start of ischemia (4.8 ± 2.0 U/mL). The serum levels of TNF in sham-operated rats (3.2 ± 0.7 U/mL) were similar to those observed before and during intestinal ischemia.

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Effects of PTX on intestinal I/R

Pulmonary effects

PTX significantly reduced the pulmonary MPO activity of rats upon intestinal I/R (Fig. 6). In rats with an intact lymphatic duct, a 78% reduction of MPO activity was observed (in untreated rats, O.D. = 0.460 ± 0.005; in treated animals, O.D. = 0.101 ± 0.012), whereas in rats in which the duct was ligated, an approximately 80% inhibition was noted (MPO in untreated rats, O.D. = 0.282 ± 0.030; in treated rats, O.D. = 0.052 ± 0.006).

PTX significantly decreased the extravasation of EB dye in lungs (untreated, 115 ± 9 μg EB/g dry weight; treated, 35.6 ± 4 μg EB/g dry weight) of rats with an intact lymphatic duct, the values being not different from those of the basal group (50 ± 6 μg EB/g dry weight; Fig. 7). The extravasation in rats with a ligated lymphatic duct was unaffected by PTX (63.7 ± 5.3 μg EB/g dry weight) relative to that observed in untreated rats (60.9 ± 5.3 μg EB/g dry weight).

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Intestinal effects

PTX prevented the increase in extravasation of EB dye in the intestine of rats subjected to intestinal I/R with an intact lymphatic duct (untreated, 255 ± 9.1 μg EB/g dry weight; treated, 72.8 ± 20 μg EB/g dry weight), but failed to do so in rats with ligated duct (Fig. 8).

The amount of intestinal LDH (Fig. 9) was significantly reduced in rats upon intestinal I/R with a preserved lymphatic duct as compared with values of basal group (I/R, 14.28 ± 1.44 U/mg; basal, 23.12 ± 3.15 U/mg). Lymphatic duct ligation increased the LDH retained in the gut (20.31 ± 1.94 U/mg) up to levels close to basal.

PTX significantly reverted the reduced amounts of LDH in rats with an intact lymphatic duct upon intestinal I/R (18.36 ± 0.9 U/mg), but failed to modify intestinal LDH of rats with ligated lymphatic duct (23.45 ± 3.0 U/mg) relative to basal levels (20.31 ± 1.94 U/mg).

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TNF levels

PTX treatment significantly reduced the TNF titers in the serum of rats after intestinal I/R, which had a preserved lymphatic duct (PTX-treated ≤ 1; untreated = 44.1 ± 8.0 U/mL). On the other hand, TNF levels in sera of rats treated with PTX and with a lymphatic duct ligated were as reduced as those found in their untreated counterparts (Fig. 10). In addition, PTX did markedly decrease the levels of TNF in the lymph to undetectable levels as compared with the untreated rats (Table 1).

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Our data show that intestinal I/R in rats caused dramatic lung neutrophil recruitment and markedly increased lung microvascular permeability. Because these events constitute important features of the pulmonary dysfunction observed in patients with ARDS, intestinal I/R as performed herein might be viewed as a valid model to study the lung injuries that follow a distant insult such as gut trauma (1, 3). In addition, local alterations were also seen after reperfusion because in the intestinal tissue there were reduction of LDH activity and increased EB dye leakage. It might be argued that these alterations could be due, at least in part, to some gut edema caused by intestinal I/R. Parallel assays to clarify specifically this point made it clear that this was not the case because the intestinal tissue dry/wet weight ratios among the groups were not significantly different.

Most interestingly, ligation of the thoracic lymphatic duct not only significantly blunted the lung alterations, but also prevented or blocked the intestinal tissue injuries due to I/R. We observed that the sera of I/R rats with intact lymphatic vessels had high amounts of TNF, and that after duct ligation these values fell down to essentially undetectable levels. In this context, it is noticeable that the lymph collected during the reperfusion period had a high TNF content compared with the low levels found before or during the ischemic period. It is highly conceivable that TNF is a surrogate of the pulmonary injuries that follow the gut insult because it has relevant inflammatory actions on lungs (26), namely increased microvascular permeability and neutrophil recruitment.

Our data confirm other studies (27, 28) that indicate that the reperfusion of an intestinal ischemic area plays a pivotal role in the induction of TNF release. In fact, to our knowledge, the present data represent a first description of the temporal profile of TNF surge in the lymph of rats subjected to intestinal I/R. Presumably, the TNF generated in the intestinal tissues upon I/R is drained through the mesenteric lymph nodes and thereby reaches the lungs. Furthermore, recent data from our laboratory demonstrated that rats subjected only to intestinal ischemia do not develop pulmonary inflammation (15).

It is of interest that, in contrast to our results showing that an ischemic gut trauma evokes release of TNF in lymph, other authors showed that the mesenteric lymph collected from animals subjected to a hemorrhagic shock did not show TNF activity (29). A brief discussion about the possible causes of this discrepancy is now in order. First, the intestinal ischemia in our I/R model is immediate because the arterial clip instantly blocks the local blood supply, whereas the hypoxic condition imposed by a hemorrhagic shock is gradually installed. Second, we used a 45-min period of ischemia, whereas in the hemorrhagic model, a 90-min experimental period was used. Third, the alterations caused by I/R are initially local in nature, and those after severe hemorrhage are due to a much more disseminated, systemic disruption of homeostasis. Finally, it must be considered that the blood supply interruption in our model constitutes a kind of local trauma far more severe than that caused by a stepwise decrease of systemic blood pressure. In conclusion, the differential pattern of cytokine release between these trauma models (30) reinforces our view that the intestinal tissue under I/R conditions may release TNF, which enters the lymphatic circulation.

Overall, there is a reasonable bulk of evidence showing that factors present in the lymph of rats subjected to intestinal I/R determine pulmonary neutrophil recruitment, a fact involving ICAM-I (8). In addition, the endothelial activation during a gut trauma appears to be mediated by lymph-borne factors (31, 32). Moreover, studies using the gut insult as a model of pulmonary injury revealed that factors present in the thoracic lymph mediate the acute lung lesions (33).

At least part of the TNF activity detected in serum after reperfusion of the intestinal ischemic area seemed to be transported by lymphatic vessels, as suggested by the high lymph/serum TNF ratios in postischemic rats with a cannulated thoracic duct (see Figures 4 and 5). The pool of that activity in serum may include TNF coming from lungs, hepatic, and other tissues, which might be stimulated by factors, originated at the initially shocked area. Because this particular point has not been directly investigated in this paper, the precise relationship between lymph effects on pulmonary microenvironment and induction of intestinal injury remains to be clarified.

Notwithstanding, two aspects appear to support the view that TNF in lymph might stimulate lung tissue to release additional mediators and thereby contribute to the intestinal injury: the lung is the first organ exposed to mesenteric lymph (7), and ligation of the lymphatic duct protected the gut, as shown by restored intestinal LDH activity (see left bars in Figure 9).

Because ligation of the gut lymphatic drainage caused only partial reductions of the altered pulmonary neutrophil recruitment (Fig. 1) and intestinal permeability (Fig. 3), there may be other, TNF-unrelated regulatory mechanisms triggered in serum and lymph that could add to the pulmonary and intestinal injuries. For instance, we have recently shown (15) that nitric oxide plays a still poorly understood regulatory role on the magnitude of lung injury in I/R.

To further explore the role of the lymphatic system as a pathway for TNF to influence the lung and gut injuries, I/R rats treated with PTX showed undetectable levels of TNF in lymph (see Table 1). In this context, these data reinforce the concept of the gut as a proinflammatory organ (7).

The pulmonary microvascular permeability (Fig. 7) and LDH activity (Fig. 9) have been shown to be closely related to TNF carried by lymphatic circulation because duct ligation brought the lung EB leakage and intestinal LDH activity to basal values, and these results were undistinguishable from that seen in PTX-treated, intact, or duct-ligated animals.

In contrast, the intestinal microvascular permeability (Fig. 8) seems to depend just partially upon lymphatic TNF because duct ligation was not capable of reducing EB leakage values to basal, regardless of the treatment with PTX. Interestingly, intact-duct rats treated with PTX had normal permeability values, an indication that some TNF-unrelated mechanisms may be put into play by the ischemic injury.

It could be argued that other properties of PTX, besides its TNF-blocking activity, could help to explain our results. In fact, PTX exerts anticoagulant, antiadhesive actions and has inhibitory effects on phosphodiesterase (34). Additionally, PTX interferes with the polarization, extravasation, and chemotaxis of neutrophils (35). Even in view of the wide range of PTX effects, we implicate the intestinal insult as the origin, and lymphatic-carried TNF as the trigger, of pulmonary inflammation, essentially in view of our data obtained with lymphatic duct ligation and the lymph content of TNF after PTX treatment.

In conclusion, our results are suggestive that TNF released after intestinal I/R mediates a series of lung alterations thereby evoked. Moreover, although TNF can be originated in organs other than intestines and lungs (e.g., the gut-liver axis via portal circulation), the results presented herein indicate that the intestinal tissue is a strong candidate for the origin of the TNF activity raised by intestinal I/R. Finally, we have shown that the lymphatic vessels constitute an important pathway for TNF to reach the pulmonary microcirculation and thence, through the blood, to contribute to the induction of the systemic inflammatory and multiple organ failure syndrome after the initial gut trauma.

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We are indebted to Dr. B. B. Vargaftig of the Department of Pharmacology of Institute of Biomedical Sciences of University of Sao Paulo for his involvement in the discussion and careful revision of this manuscript.

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KeyWords-: Gut trauma; lymph; tumor necrosis factor; neutrophils; vascular permeability; lung injury; ARDS; myeloperoxidase; pentoxifylline

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