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*Surgical Intensive Care Unit, National Cardiovascular Center; Intensive Care Unit, Osaka University Hospital; Department of Pathology, School of Allied Health Sciences, Osaka University; and §Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
Address correspondence and reprint requests to Hideaki Imanaka, MD, Surgical Intensive Care Unit, National Cardiovascular Center, Fujishiro-dai, Suita, Osaka, Japan 565. Address e-mail to imanakah{at}hsp.ncvc.go.jp
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) and profibrogenetic (transforming growth factor-ß1) mediators was analyzed at mRNA level in lung tissue. Wistar rats were ventilated by high pressure (45 cm H2O of peak inspiratory pressure, n = 23) or low pressure (7 cm H2O, n = 13) with 0 positive end-expiratory pressure. After 40 min of comparative ventilation, lung lavage was performed in 20 rats from the experimental group and 10 from the control for immunofluorescence analysis with anti-Mac-1 and anti-ICAM-1 monoclonal antibodies. The lung tissues from remaining rats were subjected to pathological and reverse transcription-polymerase chain reaction examinations. Although there was no significant change of PaO2 in the low-pressure group, PaO2 was decreased in the high-pressure group. The high-pressure group also had greater neutrophil infiltration into alveolar spaces, upregulation of CD54 and CD11b on alveolar macrophages, and more transforming growth factor-ß1 mRNA in lung tissues. Tumor necrosis factor- was not involved in the pathogenesis of the severe VILI observed. Histologic findings also demonstrated more infiltrating neutrophils, destructive change of the alveolar wall, and deposition of matrix in the high-pressure group. These results suggest that a series of proinflammatory reactions and profibrogenetic process may be involved in the course of VILI.
Implications: High-pressure ventilation demonstrated, in the early phase, not only proinflammatory processes, including neutrophil infiltration and adhesion molecules upregulation on macrophages, but profibriogenetic processes, including transforming growth factor-ß1 mRNA expression in the lung tissue. These immunological alterations may be involved in the progress of ventilator-induced lung injury.
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Several studies have suggested that inflammatory cells and mediators play an important role in the pathogenesis of VILI (6–10), as well as acute respiratory distress syndrome (ARDS) (11) and septic shock (12). In surfactant-depleted rabbits, 4 h of conventional mechanical ventilation induces severe hypoxemia and marked albumin leakage, whereas there is minimal change in neutrophil-depleted animals (7). In normal rabbits subjected to saline lavage, conventional mechanical ventilation increases lung neutrophil accumulation and chemiluminescence (13,14) as well as levels of inflammatory mediators, such as platelet activating factor and thromboxane-B2, in bronchoalveolar lavage (9) and expression of tumor necrosis factor (TNF)- in alveolar macrophage (8). More recently, it was shown that high-pressure ventilation activated proinflammatory cytokines in an ex vivo model (10). Despite the accumulating evidence that inflammatory mediators are associated with VILI, it is not known how adhesion molecules contribute to neutrophil traffic or which immune reactions are specifically involved in the pathogenesis of VILI. As a step in this direction, we investigated a potential role of neutrophils and macrophages in VILI, which are strongly associated with acute inflammation in the lungs.
The acute and persistent inflammation of the lung associated with ARDS often leads to the formation of pulmonary fibrosis, which compromises the structure of alveoli and vasculature and leads to severe functional lung impairment (15,16). There is evidence that transforming growth factor-ß1 (TGF-ß1) plays a major role in directing the cellular response to injury, promoting fibrogenesis, and thus potentially underlying the progression of tissue injury to fibrosis (17). TGF-ß1 has also been specifically implicated in the pathogenesis of pulmonary fibrosis (18) and hepatic fibrosis (19). Persistent inflammation is associated with VILI, and lung fibrosis is often found in microscopic examination of lung tissue samples taken from the victims of ARDS (15). To this end, it is important to examine whether TGF-ß1 plays a role in fibrosis seen in VILI.
In this study, our efforts were aimed at examining and comparing the expression of inflammatory molecules, including Mac-1, ICAM-1, or both, on neutrophils and macrophages isolated from lung lavage fluid samples from high- and low-pressure groups. Further, the expression of TGF-ß1-specific mRNA in the lungs of these two groups was also investigated to assess its involvement in the formation of lung fibrosis.
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After 20 cm H2O PIP ventilation, we measured baseline blood gas with a calibrated blood gas analyzer (ABL505 and OSM3; Radiometer A/S, Copenhagen, NV, Denmark) and established a static pressure-volume curve according to a previously described method (20). The lungs were inflated stepwise in 1-mL increments to 10 mL with a 2-s pause at each step. The procedure was repeated three times. Because the animals could not tolerate sustained apnea, an inflation limb of the pressure-volume curve was used for interpretation. The inflection point was defined as the pressure corresponding to the intersection of the pressure-volume curve as described previously (20). At the end of the experiment (40 min ventilation), the pressure-volume curve was again established in a similar manner.
After this, the animals were divided at random into two groups according to type of ventilation to be received: the high-pressure group (n = 23) received PIP 45 cm H2O at a rate of 20 breaths/min and an inspiratory time of 1 s; the low-pressure group (n = 13) received PIP 7 cm H2O at 60 breaths/min and an inspiratory time of 0.4 s, as described previously (1). Other variables—0 PEEP, FIO2 of 0.21, and continuous flow of 10 L/min—were the same for both groups. At 5 and 40 min into ventilation, arterial blood gas from each animal in both groups was analyzed.
Airway pressure was measured at the proximal end of the endotracheal tube with a differential pressure transducer (TP-603T, ±50 cm H2O; Nihon Kohden, Tokyo, Japan) and amplified (AR-601G; Nihon Kohden). The transducer was calibrated at 10 cm H2O with a water manometer. Arterial pressure was measured at the internal carotid artery with a disposable monitoring system (Abbott, Sligo, Ireland) and amplified (AP-601G; Nihon Kohden). The transducer was calibrated at 50 mm Hg. All signals were recorded on an IBM-compatible computer after digitization at an acquisition rate of 100 hertz per channel by using data acquisition software (Windaq; Dataq Instruments Inc, Akron, OH).
After 40 min of comparative ventilation, each animal was killed with 2 mL of pentobarbital injection and, to harvest the cells that had infiltrated into alveolar spaces, a complete lung lavage was performed on 20 animals from the high-pressure group and 10 from the low-pressure group. A 10-mL dose of phosphate-buffered saline (PBS) was instilled through the tracheostomy tube and drained after 10 s of retention. This procedure was repeated five times. To obtain counts of nucleated cells in lavage fluid samples, a hemocytometer was used. Differential cell counting was done under microscopic observation after cytocentrifuge preparations of lavage fluid were performed by Cytospin 3 (Shandon Scientific Ltd, Cheshire, UK) and were stained with Wright’s stain. Cell counts were expressed as number per rat and as a fraction of the total cell count. Because of the marked decrease in total cell numbers in the lung lavage fluid of rats in the high-pressure group, we combined the lavage fluid from pairs of animals in this group into single samples and halved the result to get a per-animal count. The remaining six animals (e.g., three rats per group) provided tissue samples for reverse transcription-polymerase chain reaction (RT-PCR).
Fluorescein isothiocyanate-conjugated mouse anti-rat CD11b ( chain of Mac-1) and phycoerythrin-conjugated mouse anti-rat CD54 (ICAM-1) monoclonal antibodies (Pharmingen Inc, San Diego, CA) were used for immunofluorescence staining. For the staining, 105 lung lavage cells were washed twice with PBS and resuspended in 50 µL of PBS containing 2% fetal bovine serum (FBS), 0.05% sodium azide, and 5 µg of monoclonal antibody. After incubation for 30 min at 4°C in the dark, cells were washed twice with PBS containing 2% FBS and 0.05% sodium azide. Then cells were resuspended in 1 mL of PBS containing 2% FBS and 1% paraformaldehyde and stored at 4°C in the dark before flow-cytometrical analysis.
Flow-cytometric measurements were made with a FACScan (Becton Dickinson, San Jose, CA). A minimum of 20,000 events was analyzed for each sample. Analysis was performed with a software application (CELLQuestTM; Becton Dickinson). Neutrophils and alveolar macrophages were separately gated according to their forward and sideward scatter. This technique showed excellent correlation to regular immunocytochemical methods (21). The expression of cell-surface molecules identified by respective monoclonal antibodies was assessed as the mean fluorescence intensity in arbitrary units. For proper comparison of the fluorescence intensity values, as described previously (22), a standard set of fluorescein isothiocyanate-calibrated microbeads and isotype-matched nonbinding antibodies (Pharmingen Inc) were included in each sample.
The remaining six rats (three from each group) were subjected to the analysis of TGF-ß1- and TNF--specific mRNA. Immediately after death, the dorsal portion of the left lower lobe (15 x 15 x 15 mm) was resected and frozen in liquid nitrogen. Each sample was homogenized, and total RNA was extracted by a previously described guanidinium isothiocyanate method (23). For the detection of cytokine-specific mRNA expression, amplification of the message was performed with SuperScriptTM Preamplification system (GibcoBRL; Gaithersburg, MD). Details of this procedure have been described elsewhere (24). The reaction protocol involves using a programmed thermal cycler (GeneAmpTM9600; Perkin Elmer Corp, Emeryville, CA) with a sequence of 35 cycles of 95°C for 1 min, 55°C for 1 min, and 72°C for 1 min. The rat PCR primers were purchased from Clontech (Palo Alto, CA). The amounts of PCR products were examined by using capillary electrophoresis with a laser-induced fluorescence detection system (LIF-P/ACETM; Beckman Instruments, Fullerton, CA). The individual peak areas were analyzed and compared to ascertain the concentration of cytokine-specific targets and ß-actin, a housekeeping gene, as a control (24).
Histologic examination was performed immediately after lung lavage was finished. The trachea and lungs were removed, the trachea was instilled and fixed immediately with 10% buffered formaldehyde (pH 7.2) at a hydrostatic pressure of 20 cm H2O, and the specimen was floated in a fixative. Paraffin-embedded sections of the lung tissues in the anterior upper and posterior lower lobes were stained with hematoxylin-eosin and then examined by a pathologist who was blinded to the protocol and experimental groups. Acute lung injury was scored according to the following four items: 1) alveolar congestion, 2) hemorrhage, 3) infiltration or aggregation of neutrophils in airspace or the vessel wall, and 4) thickness of the alveolar wall/hyaline membrane formation (25). Each item was graded according to a five-point scale: 0 = minimal (little) damage, 1+ = mild damage, 2+ = moderate damage, 3+ = severe damage, and 4+ = maximal damage (25). Connective tissue and matrix deposit were also examined by histochemical methods such as Masson trichrome staining and phosphotungstic acid hematoxylin staining.
The lung injury score data are given as median (range), whereas the other data are presented as mean ± SD. Parametric data were analyzed with one-way analysis of variance followed by post hoc analysis with Bonferroni correction. The lung injury score was analyzed with the Kruskall-Wallis rank test. P < 0.05 was considered significant. All statistical analysis was performed with a commercially available software application (SPSS; SPSS Inc, Chicago, IL).
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were examined, increased levels of TGF-ß1-specific message were noticed in lungs obtained from rats receiving high-pressure ventilation ( Fig. 4). The levels of mRNA for TNF- were slightly increased in the high-pressure group, although there was no significant difference from the low-pressure group (Fig. 4). The mRNA specific for either TGF-ß1 or TNF- was not detected in lung samples from spontaneously breathing normal rats (data not shown).
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Discussion |
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mRNA. Our in vivo model shows that high-pressure ventilation for 40 minutes causes impaired oxygenation, the appearance of lower inflection points, destructive changes in the alveolar wall, and the infiltration of neutrophils into alveolar spaces, all of which are characteristics of phenomena consistent with previous reports of VILI (1,2). To this end, Dreyfuss et al. (1) reported that ventilation with 45 cm H2O PIP resulted in pathophysiological changes in the lungs, such as the destruction of epithelial lining and basement membrane. In a follow-up study, they demonstrated that volume, rather than pressure, was a key to VILI formation (2). By using a saline lavage model, Sugiura et al. (13) and Matsuoka et al. (14) evaluated neutrophil accumulation and chemical mediators in lung lavage fluid during VILI. Their study showed that high-frequency oscillatory ventilation prevented ventilatory damage, whereas conventional mechanical ventilation caused severe damage. On the basis of these findings, it was proposed that shear stress contributes to VILI, and it was suggested that by keeping the alveoli open, PEEP may prevent the progress of VILI. These studies (13,14) were performed in surfactant-depleted animals, which may have amplified the stress related to the opening and collapse of alveoli. Overstretching of the alveoli is also crucial in VILI, and the interaction between tidal inflation and pulmonary hemodynamics is likely contributive (26,27). Although shear stress or overstretch are plausible mechanical causes, we still have little knowledge of what happens at the cellular and molecular level, such as whether the activation of cells and mediators is involved in this damage.
Adhesion molecules play an important role in ARDS (11), acid aspiration (28,29), and asthma (22). Mac-1, a member of the integrin family, is expressed on granulocytes, macrophages, and natural killer cells. When the cells are stimulated, the amount of Mac-1 expression is reported to increase. ICAM-1, in the immunoglobulin superfamily, is also upregulated when cells are activated (12,30). Thus, the expression of these adhesion molecules was analyzed in the present study because the enhancement of these cell membranous molecules is well correlated with cell activation (12). Further, these molecules are essential participants in the process of leukocyte extravasation (30). The expressions of Mac-1 and ICAM-1 were increased on individual macrophages despite the decrease in the numbers of cells in lung lavage fluids. The decreased number of macrophages in bronchoalveolar lavage fluid of acute lung injury in the high-pressure group correlates with previous reports in animal (31) as well as clinical studies (32), although the cell population in the low-pressure group was similar to a control group with no mechanical ventilation (94% macrophage, 5% lymphocyte, and 1% neutrophil). A plausible explanation for its decrease is as follows. First, macrophages may be washed out or be diluted by the pulmonary edema fluid that is induced during high-pressure ventilation. Second, macrophages may become apoptotic during the process of lung injury, resulting in a decrease in its number (33). However, the time course in this study (40 minutes) might be too short for the apoptosis. Third, it is possible that alveolar macrophages are sequestered in the interstitial space or are stuck to the alveolar epithelial cells (34,35). The upregulation of adhesion molecules—Mac-1 and ICAM-1—on macrophages may partly support this speculation. Histologic study, however, showed only minimal interstitial accumulation of macrophages in the interstitial space. Further investigation is required to elucidate the mechanism of how alveolar macrophages decrease in acute lung injury.
This is the first report of upregulation of adhesion molecules in a VILI model. This finding suggests that limited numbers of activated alveolar macrophages might play an important role in initiating the inflammation typical of VILI. These activated macrophages may immediately respond to the overdistention of alveolar tissue, attract neutrophils by releasing proinflammatory cytokines such as interleukin-8, and subsequently exacerbate tissue injury by mechanical forces in VILI. The activation of macrophages and the succeeding accumulation of neutrophils is possibly the outcome of a complicated cascade of cytokines and cell interactions, a process that incidentally leads to aggravated lung injury.
The RT-PCR findings also showed increased levels of mRNA for TGF-ß1 in the lung tissue. TGF-ß1 enhances the production of extracellular matrix, which increases during fibrosis. A previous report has shown that in vivo gene transfection of TGF-ß1 into the lung resulted in lung fibrosis (18). Thus, because damage caused by ARDS and mechanical ventilation often results in fibrotic change (16), the expression of TGF-ß1 might be implicated in the formation of fibrosis in VILI. Although the cellular source of TGF-ß1 in VILI was not specified in this study, macrophages, lung fibroblasts, and epithelial cells might produce TGF-ß1 (17,36).
A new insight from our results is that, in addition to the proinflammatory reaction such as neutrophil infiltration and upregulation of Mac-1 and ICMA-1 at the very early phase of VILI, there is induction of a profibrogenetic cytokine, TGF-ß1. Histologic findings that the deposition of extracellular matrix was observed in the high-pressure group also suggest that the profibrinogenetic process might be initiated at the early stage of VILI. Our findings provide evidence that an inflammatory reaction, including high expression of adhesion molecules and a production of profibrogenetic cytokine, can be already involved in the early phase of VILI. In this study, we found that TNF- mRNA levels in the lung tissue were not modified significantly with high-pressure ventilation. This finding correlates with the previous reports. Verbrugge et al. (37) showed no TNF- release in serum or bronchoalveolar lavage fluid after VILI by using an in vivo rat model of surfactant deficiency. Pugin and Vlahakis (38,39) demonstrated that TNF- was not induced in in vitro stretched alveolar macrophages or alveolar epithelial cells. In contrast, increased expression of TNF- mRNA is observed in lungs injured by repetitive lung lavage (8) and ex vivo in nonperfused lung models after two hours of high-pressure ventilation (10). Further study may be needed to conclude the role of TNF- in the pathogenesis of VILI in patients.
It is unclear whether inflammatory factors detected in this study cause or are merely a consequence of VILI. In ARDS, activation of neutrophils and chemical mediators has also been postulated, and antiinflammatory therapy has been partially effective in preventing the systemic changes frequently seen in ARDS (16). In a model of acid-induced lung injury, Nagase et al. (28) have reported that anti-ICAM-1 antibody partially reduced the acid-induced lung damage. These findings suggest that adhesion molecules contribute to the process of lung injury. In our VILI model, although there was an upregulation of Mac-1 and ICAM-1 on macrophage, it remains to be clarified whether VILI can be inhibited by antiinflammatory therapy, including the administration of specific monoclonal antibodies and antisense. Further, how these different phases of inflammation relate to the progress of VILI needs to be determined.
Despite its interesting results, this exploratory study was limited in several ways. In particular, our short-term model did not evaluate long-term changes in the lung. Thus, the study could not trace the fibrotic changes in different stages of VILI. Further investigation is needed to clarify the effects of mechanical ventilation on the lungs during periods of longer duration. Our in vivo animal model also did not allow us to evaluate the effect of gravity on VILI. In this study, we did not evaluate the effect of PaCO2 value on the VILI, although there is evidence showing that hypercapnia may limit lung injury (40,41). Several ventilatory strategies have been proposed to prevent VILI. Amato et al. (4) have demonstrated a strategy in which PEEP level is adjusted above the lower inflection point of the pressure-volume curve; PIP should also be kept below an upper inflection point. Recently, a large-scale multicenter trial demonstrated a 25% decreased mortality of ARDS patients in a low-tidal volume group compared with a high-tidal volume group (5). Despite these ventilatory improvements, the prognosis of ARDS remains unsatisfactory (10,42). Better understanding of the cellular and molecular mechanisms of VILI is likely a first step toward the development of a new approach for protective ventilatory procedures.
In conclusion, proinflammatory processes, including the infiltration of neutrophils and the upregulation of adhesion molecules on macrophages and profibriogenetic process, including the increased expression of TGF-ß1 mRNA, are demonstrated in lungs of VILI. These immunological alterations may be involved in the progress of VILI.
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gene during conventional and high-frequency ventilation. Am J Respir Crit Care Med 1997; 156: 272–9. and prostacyclin production in lavaged rat lungs in vivo. Anesthesiology 1999; 91: 1834–43.[ISI][Medline]
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); after 40 min ventilation (
). PIP, peak inspiratory pressure.
