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Published ahead of print on April 27, 2006, doi:10.1164/rccm.200507-1178OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 178-186, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200507-1178OC

Original Article

Ischemia and Reperfusion Increases Susceptibility to Ventilator-induced Lung Injury in Rats

Ettore Crimi, Haibo Zhang, Robin N. N. Han, Lorenzo Del Sorbo, V.Marco Ranieri and Arthur S. Slutsky

Division of Respiratory Medicine, Department of Medicine, University of Toronto; Interdepartmental Division of Critical Care Medicine, University of Toronto; Departments of Anaesthesiology and Surgery, University of Toronto; and Department of Critical Care Medicine, St. Michael's Hospital, Toronto, Ontario, Canada; Departments of Anesthesiology and Critical Care Medicine, University of Eastern Piedmont, Novara; and Sezione di Anestesiologia e Rianimazione, Dipartimento di discipline Medico-Chirurgiche, Università di Torino, Ospedale S. Giovanni Battista, Torino, Italy

Correspondence and requests for reprints should be addressed to Arthur S. Slutsky, M.D., 30 Bond Street, Room 4-042 Queen Wing, Toronto, ON, M5B 1W8 Canada. E-mail: arthur.slutsky{at}utoronto.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objectives: Hemorrhagic shock followed by resuscitation (HSR) commonly triggers an inflammatory response that leads to acute respiratory distress syndrome.

Hypothesis: HSR exacerbates mechanical stress–induced lung injury by rendering the lung more susceptible to ventilator-induced lung injury.

Methods: Rats were subjected to HSR, and were randomized into an HSR + high tidal volume and zero positive end-expiratory pressure (PEEP) or a HSR + low tidal volume with 5 cm H2O PEEP. A sham-operated rat + high tidal volume and zero PEEP served as a control.

Results: HSR increased susceptibility to ventilator-induced lung injury as evidenced by an increase in lung elastance and the wet/dry ratio and a reduction in PaO2 as compared with the other groups. The lung injury observed in the HSR + high tidal volume group was associated with a higher level of interleukin 6 in the lung and blood, increased epithelial cell apoptosis in the kidney and small intestine villi, and a tendency toward high levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatinine in plasma.

Conclusions: HSR priming renders the lung and kidney more susceptible to mechanical ventilation–induced organ injury.

Key Words: inflammation • lung mechanics • multiple organ failure

Hemorrhagic shock followed by resuscitation (HSR) frequently triggers an inflammatory response as reflected by an increased expression of numerous inflammatory mediators, including tumor necrosis factor {alpha} (TNF-{alpha}) and interleukin 6 (IL-6) (1–12). Acting as a first insult, HSR may prime the immune system to enhance a deleterious host reaction in response to a secondary stimulus. This so-called two-hit hypothesis has been tested and proven in a variety of animal models of endotoxemia after hemorrhagic shock (13–16). For example, HSR followed by intratracheal instillation of LPS increased cytokine and chemokine responses that led to lung neutrophil sequestration and injury as compared with either HSR or LPS alone (14–16).

Mechanical ventilation represents life-saving support for many patients with respiratory failure (17). However, mechanical stresses produced by mechanical ventilation can lead to ventilator-induced lung injury (VILI) (18), with generation or enhancement of an inflammatory response (19–24). Recent studies have demonstrated that VILI can be associated with decompartmentalization of inflammatory mediators (25, 26), leading to systemic inflammatory responses and possible end-organ dysfunction (27, 28). Approximately 20% of patients who have hemorrhagic shock require mechanical ventilation, but the two-hit impact has not been well addressed in terms of VILI and other end-organ failure after mechanical ventilation (29). This study tested the hypothesis that HSR renders the lung more susceptible to VILI and, ultimately, can lead to an increased systemic inflammatory response and end-organ dysfunction.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Surgical Preparation
A detailed description of surgical procedures is provided in the online supplement. Briefly, all experiments were conducted in compliance with Animal Care and Use Committee–approved protocols of St. Michael's Hospital. A tracheostomy was performed, and a 14-gauge cannula (Angiocath IV catheter, 2.1 x 48 mm; Becton Dickinson Infusion Therapy Systems, Inc., Sandy, UT) was inserted into the trachea of male Sprague-Dawley rats. The animals were ventilated with a small-animal ventilator (Voltek Enterprises, Toronto, ON, Canada) using a tidal volume (VT) of 7 ml/kg, positive end-expiratory pressure (PEEP) of 3 cm H2O, and a respiratory rate of 50 breaths/min with a fraction of inspired oxygen (FIO2) of 35 to 40%.

HSR
While the animals were being ventilated as described above, hemorrhagic shock was initiated by withdrawing blood over a period of about 15 min, until the mean arterial pressure (MAP) reached 40 mm Hg. This blood pressure was maintained by further withdrawal of blood if the MAP was greater than 45 mm Hg or by infusion of shed blood if the MAP was less than 35 mm Hg. Shed blood was collected into a 0.1% citrate preservative solution to prevent clotting.

After 15 min at this blood pressure, the animals were resuscitated by transfusion of the shed blood and lactated Ringer's solution in a 1:1 ratio, over a period of 30 min. The goal of resuscitation was to restore values of MAP to 70 to 80 mm Hg within 15 min and to maintain blood pressure at this level during the rest of the experiment.

To examine the inflammatory responses induced by HSR before further randomization to different strategies of mechanical ventilation, five animals were killed at the end of the 1-h HSR. An additional five animals served as time-matched sham controls without exposure to HSR. These animals were ventilated with the same settings as described above during HSR, and killed immediately after resuscitation.

Experimental Protocol
After HSR, the animals were randomly assigned to receive mechanical ventilation at two different VTs over a 4-h period: in group 1 (HSR + high VT [HV], n = 10), the animals were ventilated with an HV of 12 ml/kg and zero PEEP (ZEEP); in group 2 (HSR + low VT [LV], n = 10), the animals were ventilated with an LV of 6 ml/kg with PEEP of 5 cm H2O.

A third group (sham + HV, n = 10) was ventilated with an initial VT of 7 ml/kg, PEEP of 3 cm H2O, and a respiratory rate of 50 breaths/min for 1 h to serve as a time-matched group without HSR, followed by a VT of 12 ml/kg and ZEEP for 4 h.

The detailed methods regarding hemodynamic monitoring and fluid maintenance, measurement of lung mechanics and blood gases, respiratory system pressure–volume curves, sampling, measurements of cytokines and biochemical markers of organ dysfunction, apoptosis assay of lung and distal organs, lung wet/dry ratio, and statistical analysis are provided in the online supplement.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Hemodynamics and Arterial Blood Gas Exchange
MAPs for the three groups are shown in Figure 1. There was no difference in baseline among the groups, and the MAP was identical for the two groups receiving hemorrhagic shock. The volume of blood withdrawn was also similar in the hemorrhagic groups (HSR + HV, 9.2 ± 0.2 ml, vs. HSR + LV, 9.0 ± 0.2 ml; p = not significant [NS]). Fluid resuscitation restored MAP to above 100 mm Hg initially and MAP was maintained above 70 mm Hg during the 4-h ventilatory period. There was no difference in the volume of fluid infused during the 4-h ventilation (HSR + HV, 14.8 ± 0.13 ml, vs. HSR + LV, 14.7 ± 0.15 ml, vs. sham + HV, 14.2 ± 0.24 ml; p = NS for all).


Figure 1
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  		Figure 1. Time course of mean arterial pressure (MAP) during hemorrhagic shock and resuscitation (HSR; left) and after randomization to mechanical ventilation of high volume (HSR + HV, n = 10; squares), low volume (HSR + LV, n = 10; triangles), and a sham ventilated with high volume (sham + HV, n = 10; circles;right). Note: At 0 h on the right side, MAP tended to decrease immediately after positive end-expiratory pressure application in the HSR + LV group. The differences in MAP did not reach statistical significance when compared with other groups. #p < 0.01 HSR + HV versus sham + HV; °p < 0.01 HSR + LV versus sham + HV.

 
PaO2, PaCO2, pH, and Formula levels during the 4-h ventilation are shown in Figure 2. Mean values of PaO2 were similar until the third hour of ventilation in all groups. Thereafter, the HSR + HV group had a significantly lower PaO2 as compared with the HSR + LV group (82.1 ± 8.8 vs. 157.4 ± 7.0 mm Hg, p < 0.05). There was no difference in PaCO2, pH, or Formula among the HSR + HV group, the HSR + LV group, and the sham + HV group.


Figure 2
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  		Figure 2. PaO2, PaCO2, pH, and Formula during the 4-h period of ventilation after randomization. See Figure 1 legend for details. *p < 0.01 HSR + HV versus HSR + LV.

 
Respiratory Mechanics
The baseline level of lung elastance was similar in all groups (Figure 3A). At the end of the first hour of ventilation, lung elastance was significantly increased in the group receiving HSR + HV as compared with HSR + LV. At the end of the 4-h ventilation period, lung elastance was 1.53 ± 0.04 cm H2O/ml in the group receiving HSR + HV and 1.08 ± 0.037 cm H2O/ml in the group receiving HSR + LV (p < 0.001; Figure 3A). Lung elastance was also significantly higher in the sham + HV group than in the HSR + LV group (p < 0.05) between the first and third hour of ventilation; the difference did not reach significance at 4 h.


Figure 3
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  		Figure 3. (A) Elastance during the 4-h period of ventilation after randomization. See Figure 1 legend for details. *p < 0.01 HSR + HV versus HSR + LV; °p < 0.01 HSR + LV versus sham + HV. (B) Static compliance curves of total respiratory system referenced to functional residual capacity at the end of the experimental protocol. (C) Lung wet-to-dry ratio in rats not subjected to HSR (sham group, n = 5), subjected to HSR (HSR group, n = 5), subjected to HSR followed by HV ventilation (HSR + HV group, n = 10) or LV ventilation (HSR + LV group, n = 10), and not subjected to HSR but time matched followed by HV ventilation (sham + HV group, n = 10). {dagger}p < 0.01 sham versus HSR + HV; {ddagger}p < 0.01 HSR versus HSR + HV and sham + HV; *p < 0.01 HSR + HV versus HSR + LV; °p < 0.01 HSR + LV versus sham + HV.

 
It is possible that some of the measured differences in elastance were due to differences in lung volume. However, the pressure–volume curves shown in Figure 3B essentially support the concept, with the volume at a pressure of 30 cm H2O for the HSR + LV > sham + HV > HSR + LV; these track inversely with the changes in elastance in Figure 3A.

Lung Wet/Dry Ratio
The wet/dry ratio was 4.9 ± 0.08 in the sham group (p < 0.01 vs. HSR + HV), 5.3 ± 0.07 in the HSR-alone group (p < 0.01 vs. HSR + HV, and sham + HV), 6.1 ± 0.12 in the HSR + HV group (p < 0.01 vs. HSR + LV), 5.5 ± 0.1 in the HSR + LV group (p < 0.01 vs. sham + HV), and 6.0 ± 0.11 in the sham + HV group (Figure 3C).

Cytokine Responses
Lung tissue.
TNF-{alpha} levels increased in lung homogenates 2 h after HSR, and were also elevated at the end of 4-h mechanical ventilation (Figure 4). The TNF-{alpha} levels were higher in the sham + HV group than in the sham control group.


Figure 4
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  		Figure 4. Lung tissue homogenate concentrations of tumor necrosis factor {alpha} (TNF-{alpha}), interleukin 6 (IL-6), and macrophage inflammatory protein 2 (MIP-2) in the experimental groups. See Figure 3 legend for details. *p < 0.05 versus other groups; {dagger}p < 0.05 versus other groups except for sham + HV; §p < 0.05 versus sham.

 
Levels of IL-6 and macrophage inflammatory protein 2 (MIP-2) increased slightly after HSR, but these increases did not reach statistical significance. However, the levels of IL-6 and MIP-2 in lung homogenates increased dramatically in the HSR + HV group compared with the sham-operated group (both p < 0.05).

Plasma.
Plasma TNF-{alpha} level significantly increased 2 h after HSR, and returned to near baseline levels at the end of the 4-h mechanical ventilation, consistent with the short half-life of TNF-{alpha} (Figure 5).


Figure 5
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  		Figure 5. Plasma levels of TNF-{alpha}, IL-6, and MIP-2 in the experimental groups. See Figure 3 legend for details. *p < 0.05 versus other groups; #p < 0.05 versus sham and HSR.

 
Plasma levels of IL-6 and MIP-2 were unchanged after HSR but significantly increased in the HSR + HV group as compared with the other groups, with the exception that the MIP-2 level was similar between HSR + HV and sham + HV groups.

Biochemical Markers for Organ Dysfunction
HSR alone did not alter the plasma concentrations of the enzymes that were used to evaluate organ function (Figure 6). The aspartate aminotransferase levels were higher in the HSR + HV group than in any other group, and the levels of alanine aminotransferase and creatinine were higher in the HSR + HV than in sham + HV group. The levels of the biochemical markers to evaluate liver and kidney function were higher in the HSR + HV group than in the sham + HV group, but were not significantly different from the HV and LV groups after HSR.


Figure 6
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  		Figure 6. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), lactate, and creatinine. *p < 0.05 versus other groups; {dagger}p < 0.05 versus other groups except for HSR + LV.

 
It is worth noting that the blood lactate level was higher in the HSR + HV group than in the other groups (Figure 6D), whereas there was no difference in the values of pH and PaCO2 among the groups (Figure 2).

Epithelial Cell Apoptosis
Because the lung, kidney, and small intestine, but not the liver, showed some degree of apoptosis after hematoxylin-and-eosin staining, these organs were further analyzed using the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) assay. Very few or no TUNEL-positive cells were found in the lung (Figure 7), kidney (Figure 8), or intestine (Figure 9) under control conditions. In the lung, TUNEL-positive nuclei were increased in the HSR + LV group, but this increase did not reach statistical significance when compared with other groups (Figure 7). In the HSR + HV group, a significantly elevated number of TUNEL-positive tubular epithelial cells was found when compared with the sham control, HSR + LV, and sham + HV groups (p < 0.05; Figure 8). Similarly, in the small intestine villi, the number of TUNEL-positive apoptotic epithelial cells was greater in the HSR + HV group than in the sham control, HSR + LV, and sham + HV groups (p < 0.05; Figure 9). No significant difference was observed in the crypts of the small intestine.


Figure 7
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  		Figure 7. (A) Representative photomicrographs of TUNEL staining in the lung. TUNEL-positive cells are shown in green, nuclear counterstain in blue (TO-PRO3). (B) Percentage of apoptotic-positive cells; percentages obtained from 12 fields/slide x 3. Original magnification x20.

 

Figure 8
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  		Figure 8. (A) Representative photomicrographs of TUNEL staining in the kidney. TUNEL-positive cells are shown in green, nuclear counterstain in blue (TO-PRO3). (B) Percentage of apoptotic-positive cells; percentages obtained from 12 fields/slide x 3. Original magnification x20. *p < 0.05 versus other groups.

 

Figure 9
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  		Figure 9. (A) Representative photomicrographs of TUNEL staining in the small intestinal villi and crypts. TUNEL-positive cells are shown in green, nuclear counterstain in blue (TO-PRO3). (B) Total number of apoptotic-positive cells counted from 12 fields/slide x 3. Original magnification x20. *p < 0.05 versus other groups.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main findings of the present study are as follows: (1) HSR increases susceptibility to pulmonary manifestations of VILI (deterioration of pulmonary mechanics and reduced oxygenation), and is associated with enhanced systemic cytokine responses (IL-6 and MIP-2) and elevated epithelial cell apoptosis in the kidney and the villi of the small intestine; (2) in the absence of HSR, the same ventilatory strategy induced lung injury to a lesser extent; (3) HSR followed ventilation with a low tidal low volume and moderate level of PEEP were associated with less evidence of systemic manifestations.

Inflammatory Response
Hemorrhagic shock is frequently associated with cytokine responses (1–12) and can be a cause of acute respiratory distress syndrome (ARDS) (29). Previous studies have demonstrated that HSR can prime the immune system, enhancing the inflammatory response and leading to organ dysfunction when a second hit, such as LPS, is applied (14–16). Evidence from experimental models (19–25, 30–32) and clinical studies (33, 34) demonstrates that injurious ventilatory strategies can promote the release of inflammatory mediators and negatively influence the outcome of patients with acute lung injury/ARDS. We designed the current study to evaluate the effects of mechanical ventilation as a second hit after HSR. To minimize the possible hemodynamic impact on induction of organ injury and inflammatory responses, MAP was maintained at similar levels by careful adjustment of fluid infusion in all groups of animals.

We observed that plasma TNF-{alpha} increased immediately after HSR. The early release of TNF-{alpha} may have contributed to the late overall cytokine responses after mechanical ventilation. Consistent with the short half-life of TNF-{alpha} and/or complex formation with soluble receptors, no difference was found in plasma TNF-{alpha} at the end of 4-h ventilation. By contrast, plasma IL-6 levels were significantly higher when HSR was followed by ventilation with a high volume and ZEEP. IL-6 is a multifunctional cytokine induced by TNF-{alpha} (11), which participates in acute inflammatory responses, and also promotes recruitment of neutrophils to injured tissue sites by induction of MIP-2, an analog of human IL-8 (35). Although the direct consequences of the cytokine responses in relation to VILI and distal organ dysfunction were not addressed in the present study, previous studies have demonstrated that increased blood level of cytokines (i.e., TNF-{alpha}, IL-6, and IL-8) were correlated with mortality rate in patients with ARDS (36). Also, the patients with ARDS ventilated with LV had an improved survival rate, which was associated with a decrease in blood IL-6 levels (34). These data do not prove the exact role of cytokine levels but are suggestive of their importance.

One might expect to see greater differences in cytokine responses and end-organ dysfunction among the animals ventilated with HV and ZEEP compared with those ventilated with LV with PEEP of 5 cm H2O, after HSR. Several factors might explain why the differences were smaller than expected. First, the sample size of 10 was relatively small in the ventilated groups. Second, we used a VT that was only moderately high to simulate more closely the clinical setting. Higher VTs or prolonged ventilation may be required to achieve a greater signal (21, 24). Third, the hemorrhagic shock model does not induce a severe direct lung injury, as opposed to other models, such as intratracheal acid instillation. Taken together, these data suggest that early TNF-{alpha} release is required during HSR to increase susceptibility to VILI, but mechanical ventilation itself has inflammatory consequences.

A large body of evidence from animal experimental studies has demonstrated that mechanical ventilation per se can induce inflammatory responses (20–26). A recent randomized clinical trial demonstrated that the concentration of proinflammatory cytokines, including IL-1beta, TNF-{alpha}, and IL-6, remained high in lung lavage fluid of patients with ARDS receiving HV mechanical ventilation and PEEP at a level that was set to obtain the greatest improvement in arterial oxygen saturation, whereas an LV ventilatory strategy with PEEP levels that were applied based on volume–pressure curves decreased the levels of these cytokines (33). The ARDS Network study reported a lower plasma IL-6 concentration in patients with ARDS ventilated with LV than in those patients ventilated with HV (34, 37). In addition, there is a good correlation between changes in plasma IL-6 concentrations and the development of multiple-system organ dysfunction (38) in patients with acute lung injury/ARDS.

Lung Injury
We wanted to test the hypothesis that HSR can prime the immune system, thus rendering the lung more susceptible to an inappropriate ventilatory strategy. To achieve a large-enough signal in the in vivo model, we used a lung protective strategy combining LV with PEEP to minimize further injury after HSR, as compared with an injurious strategy of HV without PEEP. This concept of PEEP protection is supported by several previous studies demonstrating that the use of PEEP resulted in decreased microatelectatic area and atelectrauma. In contrast, ventilation with HV and low or zero PEEP appears to cause lung damage (39, 40), which can be attenuated by the application of PEEP (20, 24, 41, 42). The ventilatory settings used in the present study are not uncommon in clinical and experimental reports. Ventilatory strategies using HVs of 10 ml/kg or greater with ZEEP are still frequently used in general anesthesia (43–47). During trauma surgery, especially in patients with hemorrhagic shock, prolonged mechanical ventilation at HV and low or zero PEEP can predispose patients to the development of postoperative lung injury (48). In experimental studies, mechanical ventilation at a VT of 10 ml/kg and ZEEP induced lung injury in otherwise healthy lungs associated with inflammatory responses that led to transient endotoxemia (49).

Our data support the hypothesis that HSR can produce a priming effect in which exposure to a mechanical stress with high volume boosts inflammatory responses. This is reflected by accelerated lung injury, increased respiratory elastance, and reduced oxygenation. The animals ventilated with HV after HSR had significantly higher levels of plasma lactate as seen in patients with ARDS as a result of persistent lung injury (50–52).

We also found that a large VT with ZEEP tended to cause injury to otherwise healthy lungs that were not subjected to HSR. This observation is consistent with a recent experimental study showing that mechanical ventilation using a moderate VT (10 ml/kg) and ZEEP initiated a proinflammatory stimulus to the lungs, resulting in up-regulation of gene transcription of the cytokines TNF-{alpha}, IL-1beta, and the chemokine monocyte chemoattractant protein 1 (MCP-1) (53). In a recent retrospective human study, Gajic and colleagues reported a strong association between the use of large VTs and the development of acute lung injury in patients who had no lung injury before mechanical ventilation (54).

There were very small changes between the two groups in terms of HCO3 over time. In terms of blood lactate, the LV group essentially remained unchanged, whereas the HV group had an increase of about 2 mEq/L of blood lactate. This small change might not cause significant change in pH. Therefore, our results show no significant negative correlation of lactate signal with pH. A possible explanation is that most lactate is produced in well-perfused regions with viable cells and that, in these regions, H+ can diffuse away to the bloodstream more readily than can lactate. Also, excess lactate may be better related to the oxygen deficit and less subject to the pH effect on glycolysis, and ratio of excess lactate rate to true oxygen deficit rate is independent of pH (55). In addition, one approach in the present study design was to keep PaCO2 similar among groups by adding a dead space in the groups ventilated with HV and by increasing the respiratory rate in the LV groups. This approach helped to exclude possible protective effects of hypercapnia in the experimental settings.

Epithelial Cell Apoptosis and Organ Dysfunction
One of the mechanisms by which VILI may lead to distal organ dysfunction is by increasing epithelial cell apoptosis in some of these organs. In the present study, a short period of HSR did not cause any increase in apoptosis. However, ventilation with HV after HSR induced a marked increase in kidney and villi apoptotic epithelial cells, suggesting that mechanical ventilation with HV plays an important role in this process. The increased apoptosis in the kidney was associated with a tendency toward an increased level of plasma creatinine, suggesting kidney dysfunction, a common clinical manifestation in patients with ARDS (56, 57). We believe that the increase in creatinine was due to ventilatory strategy but may also be affected by potential diffuse damage to muscle in this model, because serum creatinine can increase temporarily as a result of muscle damage after reperfusion injury in skeletal muscle (58). We also demonstrated that mechanical ventilation with HV induced apoptosis in epithelial cells of the villi of the small intestine after HSR. In turn, gut apoptosis could lead to bacterial translocation worsening systemic inflammation that promotes multiple organ dysfunction (59–61). Our results are in accord with a recent study reported by our group showing that mechanical ventilation with HV and low PEEP led to increased epithelial cell apoptosis in the kidney and small intestine associated with a significant increase of plasma creatinine in a rabbit acid aspiration model of acute lung injury (27). In the previous study, we proposed that HV ventilatory strategies can lead to translocation of soluble Fas ligand from the lungs to systemic compartments, leading to multiple organ apoptosis (27). As in this previous study, we found decreased apoptosis in the lungs undergoing ventilation with the injurious strategy after HSR, possibly related to increased necrosis of epithelial cells produced by severe injury induced by mechanical ventilation as reported previously in other models (27). There was no evidence that the liver histology was significantly altered, although the levels of enzymes tended to be higher in the animals ventilated with HV compared with those ventilated with LV after HSR, suggesting that the liver might be significantly impaired in the present experimental model.

CONCLUSIONS
HSR is a significant priming factor for lung inflammation, increasing the lung's susceptibility to a secondary insult by mechanical ventilation. This leads to severe lung damage, and is associated with changes in the kidney and the small intestine. Patients with hemorrhagic shock could be at high risk of developing VILI and its potential sequelae (i.e., multiple organ dysfunction). The present study suggests that hemorrhagic shock makes the lungs more susceptible to the development of VILI and distal organ failure. It is unclear whether these results will be true in humans; however, it seems prudent to ensure that a lung protective strategy is used in the clinical setting in patients with hemorrhagic shock. Further studies are warranted to investigate potential antiinflammatory therapies in the context of resuscitation and VILI.


   FOOTNOTES
 
Supported by Canadian Institutes of Health Research (CIHR) grants MA-8558 to A.S.S., MOP-69042 to H.Z., and an infrastructure grant from the Canadian Foundation for Innovation (CFI). H.Z is a recipient of a CIHR New Investigator Award.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200507-1178OC on April 27, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form July 29, 2005; accepted in final form April 26, 2006


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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