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van Zoelen, Marieke A.D.*†; Ishizaka, Akitoshi; Wolthuis, Esther K.§∥; Choi, Goda§¶; van der Poll, Tom*†¶; Schultz, Marcus J.§**

doi: 10.1097/SHK.0b013e318157eddd
Clinical Aspects

ABSTRACT: High-mobility group box (HMGB) 1 is a recently discovered proinflammatory mediator that contributes to acute lung injury. We determined HMGB-1 levels in bronchoalveolar lavage fluid of patients during mechanical ventilation (MV) and ventilator-associated pneumonia (VAP). Bronchoalveolar lavage fluid was obtained from patients who were ventilated for 5 h because of an elective surgical procedure ("short-term MV"; n = 40) or for several days because of respiratory failure without acute lung injury ("long-term MV"; n = 10) and from patients who developed unilateral VAP (n = 4). Ten healthy volunteers served as controls. In healthy volunteers, HMGB-1 levels were low (median, 1.6 ng mL−1; interquartile range [IQR], 0.7 - 3.7 ng mL−1). Although HMGB-1 levels were elevated after short-term MV, differences were not statistically significant compared with healthy volunteers (1.7 ng mL−1; IQR, 0.8 - 8.5 ng mL−1, P = 0.493 vs. healthy volunteers; P = 0.250 vs. start of MV). However, HMGB-1 levels were significantly higher in "long-term" MV patients (11.7 ng mL−1; IQR, 8.7 - 37.0 ng mL−1; P < 0.0001 vs. healthy volunteers). With unilateral VAP, HMGB-1 levels from the infected lung were 17.4 (IQR, 8.5 - 23.2) ng mL−1 (P = 0.014 vs. healthy controls); these levels were not different from those measured in the contralateral noninfected lung (P = 0.625). Summarized, long-term MV is associated with increased HMGB-1 levels in contrast to "short-term" MV. In addition, HMGB-1 levels during VAP are increased compared with healthy volunteers; however, they are not different from those found in patients intubated and mechanically ventilated for a similar period of time.

*Center for Infection and Immunity Amsterdam (CINIMA) and Center for Experimental and Molecular Medicine (CEMM), University of Amsterdam, Amsterdam, The Netherlands; Department of Pulmonology, Keio University, Tokyo, Japan; §Laboratory of Experimental Intensive Care and Anesthesiology (LEICA); Departments of Anesthesiology, Internal Medicine, and #Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Received 4 Jun 2007; first review completed 25 Jun 2007; accepted in final form 1 Aug 2007

Address reprint requests to Marieke A.D. van Zoelen, MD, Academic Medical Center, Room G2-132, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail:

This work has been performed at the Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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Mechanical ventilation may aggravate preexisting lung injury or even initiate pulmonary damage in patients without lung injury at the start of mechanical ventilation (MV; a phenomenon referred to as ventilator-associated lung injury) (1, 2). The mechanisms underlying ventilator-associated lung injury are beginning to be understood despite the difficulties in distinguishing the effects of MV from those of underlying diseases for which MV was started. Similar to acute lung injury/acute respiratory distress syndrome (ARDS) and pneumonia, ventilator-associated lung injury is associated with local production of proinflammatory mediators. Indeed, during ventilator-induced lung injury, the experimental counterpart of ventilator-associated lung injury, cytokines, are released in the pulmonary compartment (3-5). These ventilation-induced proinflammatory changes have been confirmed in clinical studies in patients with (6-9) and without acute lung injury/ARDS at onset of MV (10).

High-mobility group box (HMGB) 1 is a recently discovered mediator of proinflammatory responses that contributes to acute lung injury (11-13). Local and systemic levels of HMGB-1 were found increased in mice that were instilled with LPS via the airways (11). In addition, acute lung injury induced by either LPS (intranasally or intratracheally), cecal ligation puncture, or pancreatitis was diminished by administration of anti-HMGB-1 antibodies (11, 12, 14, 15). Furthermore, intratracheal administration of HMGB-1 has been found to induce acute lung injury (11, 12). Finally, in rabbits, bronchoalveolar lavage (BAL) fluid (BALF) levels of HMGB-1 were 5-fold higher after 4 h of MV with large tidal volumes as compared with lower tidal volumes. In this ventilator-associated lung injury model, the administration of anti-HMGB-1 antibodies attenuated lung injury (16).

The aim of this study was to investigate the local release of HMGB-1 in the pulmonary compartment during MV and ventilator-associated pneumonia (VAP). For this, we obtained BALF from patients on "short-term" (hours) MV and "long-term" (days) MV without evidence of preexisting lung injury and from patients who developed VAP during the course of MV. Healthy volunteers served as controls.

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Study design

We collected BALF samples of patients in one prospective investigation on unilateral VAP (17) and one randomized controlled trial in which patients were randomized to be mechanically ventilated with a lung-protective ventilation strategy or a conventional ventilation strategy (see below) (18). Patients were only eligible for participation in these two studies if they had no history of any lung disease, use of immunosuppressive medication, recent infections, previous thromboembolic disease, and recent ventilatory support. The separate protocols were reviewed and approved by the Medical Ethics Committee of the University of Amsterdam, Amsterdam, The Netherlands. Written informed consent from all patients/closest relatives or volunteers was obtained before inclusion.

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Healthy volunteers were all nonsmoking individuals, whereas short-term MV patients were patients who were expected to be intubated and mechanically ventilated for at least 5 h because of elective surgery. All patients received anesthesia according to a local protocol, including intravenous propofol (induction with 2-3 mg kg−1, thereafter 6-12 mg kg−1 h−1), fentanyl (induction with 2-3 µg kg−1, thereafter as required), rocuronium (as required), and epidural bupivacaine (0.125%)-fentanyl (2.5 µg mL−1). The ventilatory protocol consisted of volume-controlled MV at an inspired oxygen fraction of 0.40 inspiratory to expiratory ratio of 1:2 and a respiratory rate to achieve normocapnia. Patients were randomized to a lung-protective MV strategy using lower tidal volumes of 6 mL kg−1 ideal body weight and positive end-expiratory pressure (PEEP) of 10 cm H2O or a conventional strategy with higher tidal volumes of 12 mL kg−1 ideal body weight and no PEEP.

Long-term MV patients were patients ventilated according to a strict local protocol in which optimal PEEP was defined as the lowest level of PEEP with maximum Pao2; in addition, patients were mechanically ventilated with tidal volumes less than 8 mL kg−1 ideal body weight.

Unilateral VAP patients were patients admitted to the intensive care unit for ventilatory support. None of the patients had evidence of acute lung injury/ARDS at the start of MV. Patients were eligible for this study when they fulfilled the following criteria: fever or hypothermia (temperature <35.0°C or >37.7°C), leukocytosis or leucopenia (leukocyte count <3 or >10 × 109 L−1), worsening of arterial oxygen tension (Pao2-Fio2 ratio) and a chest radiograph suspect for a novel unilateral infiltrate. Furthermore, the diagnosis had to be supported by the results of microbiological culture of BALF or a clinical course consistent with VAP. For safety reasons, patients were excluded with Pao2 of 10 kPa or less and Fio2 greater than 0.60. Mechanical ventilation settings were similar to those in long-term ventilation patients.

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Lung compliance

In mechanically ventilated subjects, lung compliance was calculated by dividing the tidal volume with end-inspiratory plateau pressure-PEEP difference.

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Bronchoalveolar lavage

Bronchoalveolar lavage was performed by experienced pulmonologists in a standardized fashion according to the guidelines of the American Thoracic Society by use of a flexible fiber-optic video bronchoscope. Seven successive 20-mL aliquots of prewarmed 0.9% saline were instilled in a subsegment of the lung, and each was aspirated immediately with low suction. In general, 10 to 15 mL of the instilled 20 mL was recovered. There was no difference between the recovered volumes between the different groups.

For healthy volunteers and long-term MV patients, BALF was obtained from the right middle lobe. For short-term ventilation patients, bronchoscopy and BAL were performed twice on all patients: the first just after initiation of ventilation in either the right middle lobe or the lingula and the second performed in the contralateral lung 5 h thereafter either perioperatively or directly postoperatively. For VAP patients, BAL was initiated at the noninfected lung in a subsegment of the middle lobe or lingula, followed by a lavage of a subsegment of the infected lobe, as localized on a chest radiograph.

Healthy volunteers received local application of lidocaine (in throat, near vocal cords) before introduction of the bronchoscope before the lavage. Short-term MV patients were under general anesthesia with propofol and fentanyl-no additive medication was given before the lavage. Ventilator-associated pneumonia patients were sedated with midazolam and morphine, and no additive medication was initiated because of the lavage.

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Specimen processing

Bronchoalveolar lavage fluid was kept at 4°C until processing, which was performed within 30 min. The first aliquot was discarded; the second and third BALF recoveries from both sides were sent for microbial culture and virus isolation. The remaining BALF was centrifuged, and cell-free supernatants were stored at -80°C until HMGB-1 levels were determined.

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HMGB-1 measurements

Measurements of HMGB1 in BALF were performed by enzyme-linked immunosorbent assay with the use of monoclonal antibodies to HMGB-1 and with standardization to a curve of recombinant human HMGB-1 as described previously (19). Briefly, polystyrene microtiter plates were coated with monoclonal anticalf HMGB-1 antibody. Wells were incubated with bovine serum albumin, washed, and the calibrator and samples were added to the wells. After washing, another antihuman HMGB-1 peroxidase-conjugated monoclonal antibody (a synthetic peptide was used as immunogen) was added to each well. After another washing step, the luminescence reagent was added to the wells. The luminescence was measured using a microplate luminescence reader.

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Statistical analysis

All data are presented as means and standard deviations or number (percentage) except for HMGB-1 levels: these are presented as medians (interquartile range [IQR]). Differences in HMGB-1 levels between groups were analyzed using the Mann-Whitney U test. Wilcoxon signed-rank test was used for paired BALF samples comparing t = 5 vs. t = 0 h and comparing infected versus noninfected lungs. Because no differences were found in pulmonary HMGB-1 levels between patients mechanically ventilated with lung-protective MV and with conventional MV, the data of these patients are taken together in the statistical analysis and presentation of data. Correlations were calculated using Spearman ρ test. A P value ≤ 0.05 was considered statistically significant.

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Patient characteristics are given in Table 1. Baseline characteristics and perioperative parameters in short-term MV patients were described in detail previously (18). In short, 74 consecutive patients who were scheduled for an elective surgical procedure of at least 5 h were screened in the period December 2003 to March 2005; 48 patients were excluded, leaving 46 patients for randomization. Five patients were randomized but excluded from final analysis because the initial surgical procedure was converted by the surgeon into another shorter operation (<3 h), and only one BAL was performed. One patient was randomized, but no lavages were performed upon the surgeon's request after induction of anesthesia. In total, 40 patients completed the study protocol; 21 patients were assigned to lung-protective MV strategy and 19 patients to conventional strategy. There were no major differences between both randomization groups with regard to baseline characteristics. Baseline characteristics and reasons for initiation of MV of long-term ventilation patients have been described before (17-20). In summary, 10 intubated and mechanically ventilated patients without any signs of pulmonary infection or acute lung injury/ARDS and 4 patients with unilateral VAP were recruited. These four VAP patients recovered uneventfully with antibiotic therapy.

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Mechanical ventilation

Healthy volunteers were neither intubated nor mechanically ventilated. Duration of MV for short-term MV patients was 306 ± 44 min (mean ± SD). Duration of MV in long-term MV and VAP patients at the moment of BALF collection was 7.6 ± 2.6 and 9.3 ± 3.6 days, respectively. Tidal volumes and PEEP levels in the three MV groups were in accordance with the study protocol (short-term MV) or the local MV guideline. Neither long-term MV nor VAP patients developed acute lung injury during the course of MV.

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Bronchoalveolar lavage

There were no reported adverse events related to the BAL in any study group.

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HMGB-1 levels during MV

High-mobility group box 1 levels in healthy volunteers were 1.6 [IQR, 0.7 - 3.7] ng mL−1 (Fig. 1). Patients who were intubated and mechanically ventilated for a short period had increased HMGB-1 levels directly after intubation and start of MV, although differences were not statistically significant (4.8 [IQR, 0.7 - 15.1] ng mL−1; P = 0.147 vs. healthy volunteers). In addition, HMGB-1 levels did not change during 5 h of MV (1.7 [IQR, 0.8 - 8.5] ng mL−1; P = 0.493 vs. healthy volunteers; P = 0.250 vs. start of MV). There was no correlation between HMGB-1 levels and lung compliance (data not shown). In contrast, long-term MV was associated with elevated HMGB-1 levels (11.7 [IQR, 8.7 - 37.0] ng mL−1; P < 0.0001 vs. healthy volunteers).

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HMGB-1 levels in BALF with VAP

Although increased HMGB-1 levels were found with VAP (17.4 [IQR, 8.5 - 23.2] ng mL−1; P = 0.014 vs. healthy volunteers), no differences existed between BALF levels from the infected and the contralateral, noninfected site (6.1 [IQR, 5.8 - 13.2] ng mL−1; P = 0.625 vs. infected site; Fig. 2). Moreover, HMGB-1 levels in VAP patients did not differ from those in patients on long-term MV without pulmonary infection (P = 0.839).

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The main finding of our study is that MV is associated with increased HMGB-1 levels in BALF in patients without preexistent lung injury. Second, we report here that VAP does not result in different HMGB-1 levels compared with MV alone, whereas similar MV settings were used for a comparable period.

Our results extend, at least in part, previous experimental and clinical investigations in finding increased HMGB-1 levels in the bronchoalveolar space during lung injury. First, HMGB-1 in BALF is increased in murine models of LPS or hemorrhage-induced lung injury (11, 13) and in a mouse model of ventilator-induced lung injury (16). Second, HMGB-1 in pulmonary epithelial lining fluid is elevated in septic patients with acute lung injury/ARDS (11). One limitation of this last study is that it leaves unanswered to what extent the observed elevated HMGB-1 levels in patients with acute lung injury/ARDS are induced by MV. We report here for the first time that MV itself is associated with elevated HMGB-1 levels in patients without lung injury at onset of MV.

Little is known about the role of extracellular HMGB-1 in the alveolar space in healthy and diseased lungs. Two earlier published studies showed that intratracheally or intranasally administered HMGB-1 itself causes acute lung injury in mice, manifested by neutrophil accumulation, interstitial edema, and hemorrhages in the lungs (11, 12). Moreover, Ogawa et al. (16) showed that blocking endogenous HMGB-1 in a rabbit model of ventilator-induced lung injury improved oxygenation and limited microvascular permeability and neutrophil influx into the alveolar lumen, implicating HMGB-1 as a deteriorating factor during the development of ventilator-induced lung injury and as an appropriate therapeutic target in ventilator-induced lung injury.

Besides its potential harmful role, HMGB-1 has been suggested to have a physiological role in the host defense. Zetterstrom et al. (21) suggested that HMGB-1 may contribute to the local antibacterial barrier system in the upper airways. Furthermore, healthy subjects have 1,000-fold higher HMGB-1 levels in their pulmonary epithelial lining fluid than in their plasma (11). These HMGB-1 epithelial lining fluid concentrations of healthy subjects were comparable with those of patients during the acute phase of acute lung injury/ARDS. Remarkably, this phenomenon was not found in plasma: HMGB-1 plasma levels were not or hardly detectable in healthy subjects, whereas patients with acute lung injury/ARDS with sepsis had clearly elevated HMGB-1 plasma levels. Therefore, whereas HMGB-1 is not detectable in plasma from healthy subjects and is increased in plasma form septic patients, HMGB-1 is ("abundantly") present in the bronchoalveolar space from healthy subjects as much as in patients during their acute phase of acute lung injury/ARDS. A function of HMGB-1 in the bronchoalveolar space in healthy lungs can underlie this phenomenon. Further investigations are warranted to investigate possible functions of extracellular pulmonary HMGB-1 in healthy and diseased lungs.

Although HMGB-1 levels were clearly elevated in our study several days after the start of MV (long term), a shorter duration of MV (short term) did not lead to statistically significant higher HMGB-1 levels compared with levels from either healthy volunteers or directly after intubation. This finding is in line with a recent study on HMGB-1 involvement during ventilator-induced lung injury in rabbits (16) in which ventilation during 4 h with tidal volumes of 8 mL kg−1 in rabbits did not result in elevated BALF levels of HMGB-1 relative to control rabbits. Notwithstanding, BALF HMGB-1 levels were 5-fold higher after 4 h of MV with large tidal volumes (i.e., 30 mL kg−1) as compared with the lower tidal volumes (8 mL kg−1) in this rabbit study. In the clinical setting, tidal volumes are never as high as this; moreover, the tidal volumes in patients with acute lung injury/ARDS are advised not to exceed 6 mL kg−1 (22). Whether suffering from acute lung injury/ARDS or not, we extended these findings to all patients in the intensive care unit. Therefore, all individuals included in this analysis, except for those on conventional ventilation settings during short-term ventilation, were ventilated with "lower" tidal volumes. The results from our patient study with short-term MV together with the observation from the rabbit study suggest that, in contrast to ventilation for a longer period (i.e., days), HMGB-1 does not play a major role during ventilation for a short duration (i.e., hours) with tidal volumes of 6 to 12 mL kg−1.

In our study, VAP patients had higher HMGB-1 BALF levels compared with healthy volunteers, similar to the long-term MV patients who did not develop VAP. In addition, HMGB-1 in BALF from the infected site from VAP patients was not altered compared with the contralateral, noninfected site; neither was it compared with levels of long-term MV patients who did not develop VAP. However, it remains inconclusive from these data whether there is an additional or synergistic effect of VAP on MV-induced HMGB1 levels because we did not measure HMGB-1 in the VAP patients before they developed VAP. In addition, a possible role of HMGB-1 as an antibacterial factor (21) can implicate lower HMGB-1 levels before or during the development of VAP. We did not find decreased levels in patients with already-established VAP here. It remains to be elucidated whether lower BALF levels of HMGB-1 are associated with an increased risk of developing VAP.

Because MV itself can induce lung injury, including histopathological changes and the production of proinflammatory cytokines and chemokines such as TNF-α, IL-6, and IL-8, it is of interest to compare these inflammatory changes with local HMGB-1 levels. The design of our studies did not allow us to obtain lung tissue for histopathological evaluation. We measured, however, levels of various cytokines, chemokines, markers of neutrophil activation, and proteins involved with fibrin turnover. We reported on these values before (17, 18, 23). We found neither a correlation between HMGB-1 levels in BALF and levels of various cytokines, chemokines, and markers of neutrophil activation nor a correlation with proteins involved in fibrin turnover.

In conclusion, MV itself is associated with increased HMGB-1 levels in the alveolar space in patients without preexistent lung injury. Furthermore, bronchoalveolar HMGB-1 concentrations during VAP were elevated compared with healthy volunteers but not when compared with intubated and mechanically ventilated patients who did not develop VAP. Further studies are needed to investigate the role of HMGB1 during MV, VAP, and acute lung injury/ARDS and its potential as a therapeutic target herein.

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HMGB-1; mechanical ventilation; ventilator-associated lung injury; ventilator-induced lung injury; ventilator-associated pneumonia; bronchoalveolar lavage fluid

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