Published ahead of print on May 13, 2004, doi:10.1164/rccm.200401-023OC
American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 613-620, (2004)
© 2004 American Thoracic Society
Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury
Tamás Dolinay,
Mária Szilasi,
Mingyao Liu and
Augustine M. K. Choi
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pulmonary Medicine, University of Debrecen, Debrecen, Hungary; and Thoracic Surgery Research Laboratory, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
Correspondence and requests for reprints should be addressed to Augustine M. K. Choi, M.D., Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213. E-mail: choiam{at}upmc.edu
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ABSTRACT
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Ventilator-induced lung injury (VILI) is a major cause of morbidity and mortality in intensive care units. The stress-inducible gene product, heme oxygenase-1, and carbon monoxide (CO), a major by-product of heme oxygenase catalysis of heme, have been shown to confer potent antiinflammatory effects in models of tissue and cellular injury. In this study, we observed increased expression of heme oxygenase-1 mRNA and protein in a rat model of VILI. To assess the physiologic function of heme oxygenase-1 induction in VILI, we determined whether low concentration of inhaled CO could serve to protect the lung against VILI. Low concentration of inhaled CO significantly reduced tumor necrosis factor- levels and total cell count in lavage fluid, while simultaneously elevating levels of antiinflammatory interleukin-10 levels. To better characterize the mechanism of CO-mediated antiinflammatory effects, we examined key signaling pathways, which may mediate CO-induced antiinflammatory effects. We demonstrate that inhaled CO exerts antiinflammatory effects in VILI via the p38 mitogen-activated protein kinase pathway but independent of activator protein-1 and nuclear factor- B pathways. Our data lead to a tempting speculation that inhaled CO might be useful in minimizing VILI.
Key Words: cytokines • heme oxygenase-1 • p38 MAPK
According to an international study, an average of 39% of intensive care unit patients requires mechanical ventilation worldwide (1). Many of these patients develop ventilator-induced lung injury (VILI) (2). Eventually VILI contributes to acute respiratory distress syndrome (ARDS), which has a 40 to 50% mortality rate (3). Although clinical trials showed that ARDS/VILI-related mortality could be attenuated with lower tidal volume ventilation, positive end-expiratory pressure (PEEP) ventilation, and more recently, with recruitment maneuver combined with protective ventilation strategy, the syndrome remains a major problem in intensive care units (3–5).
It is established that mechanical ventilators that apply high volumes and pressures can lead to increased alveolar–capillary permeability (6). This loss of compartmentalization results in increased fluid influx to the alveoli from the capillaries, causing pulmonary edema. The injured or ruptured cells attract neutrophil leukocytes and activate alveolar macrophages, causing inflammation in the lung (6). Tremblay and colleagues have suggested that ventilation can provoke an inflammatory response in the distal airway and alveolar cells (7), manifested by increased production of proinflammatory cytokines. It is speculated that the released proinflammatory cytokines could enter the circulation causing inflammation in other systemic organs. In addition, the previously diseased or injured lungs are more susceptible to subsequent mechanical ventilation, releasing more proinflammatory cytokines than healthy lungs, perhaps reflecting the cumulative effects of multiple injuries (8, 9). Lipopolysaccharide (LPS), acid aspiration, and cecal ligation/perforation–induced sepsis are commonly used models for approximating previous lung injury in VILI models (10–12).
Accumulating data exist in the literature supporting the paradigm that the stress-inducible heme oxygenase-1 (HO-1), or its catalytic by-product, carbon monoxide (CO), can confer potent cytoprotective effects in various models of tissue and cellular injury (13–19). One mechanism by which HO-1 or CO mediate a cytoprotective effect is via its potent antiinflammatory properties (13, 14). Our laboratory has recently demonstrated that exogenous administration of low concentration of inhaled CO can markedly decrease lung inflammation and confer potent cytoprotection in various tissue injury models (15–19).
The primary goal of the present study was to test the hypothesis that inhaled CO can confer protective effects in an animal model of VILI. We used intravenous LPS injection and/or a relatively injurious ventilator setting to induce lung inflammation, in ventilated animals in the presence or absence of inhaled CO. A protective effect of CO was observed. We then describe the potential mechanism by which CO confers antiinflammatory effects against VILI. Some of the results of these studies have been previously reported in the form of an abstract (20).
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METHODS
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Animal Preparation
For more details see the online data supplement (Table 1E).
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TABLE 1. Total and differential cell count in balf after lps treatment and 2 or 4 hours of mechanical ventilation with and without carbon monoxide
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Adult 275- to 375-g male Sprague-Dawley rats (n = 88) were purchased from Harlan (Indianapolis, IN). Rats were allowed to acclimate for 1 week with rodent chow and water ad libitum before experimentations. All animals were housed in accordance with guidelines from the American Association for Laboratory Animal Care. The Animal Care and Use Committee of the University of Pittsburgh approved the protocols.
Animals received either 3 mg/kg Escherichia coli bacterium LPS, Serotype O127: BO (Sigma, St. Louis, MO) in 0.25 ml phosphate-buffered saline (PBS) or PBS alone, injected into the tail vein under ketamine (75 mg/kg) and acepromazine (2.5 mg/kg) intraperitoneal anesthesia (Sigma). After 1 hour of spontaneous breathing, tracheotomy was performed and a canula was inserted into the trachea. We designed seven experimental conditions: control, LPS, ventilation, ventilation/CO, LPS/ventilation, LPS/ventilation/CO, and SB203580/LPS/ventilation/CO (n = 6/condition). Pairs of CO-treated and nontreated animals were formed and treated one after another. Animals treated according to condition ventilation, ventilation/CO, LPS/ventilation, LPS/ventilation/CO, and SB203580/LPS/ventilation/CO received 26 ml/kg VT mechanical ventilation with room air or with 250 ppm (ppm) CO mixed with room air for 15 minutes to 4 hours without PEEP. Condition SB203580/LPS/ventilation/CO animals were injected intraperitoneally with SB203580 p38-kinase inhibitor (20 mg/kg) 30 minutes before the experiment (21).
Arterial blood pressure and arterial blood gases were measured in condition LPS/ventilation and LPS/ventilation/CO (pressure transducer UFI, Morro Bay, CA; blood gas analyzer Radiometer ABL5, Copenhagen, Denmark).
CO Dose–Response Experiment
LPS/ventilation/CO-treated animals received 10, 100, or 250 ppm CO (n = 3–6/dose). The concentration of CO was adjusted via a flow meter; the mixed gas runs to a chamber, which was connected to the rodent ventilator.
Cellular Assays (ELISA, Western and Northern Blots)
The cytokine analysis of bronchoalveolar lavage fluid (BALF) was performed as described, using rat-specific kits (R&D, Minneapolis, MN) (7). Total protein concentration was determined with Coomassie Plus 200 Protein Assay (Pierce, Rockford, IL). Western blot analysis was performed as previously described for HO-1 and p38 MAPK phosphorylation (18). Total cellular RNA was extracted from lung tissue and Northern blot analysis was performed for HO-1 gene expression as previously described (17).
Electrophoretic Mobility Shift Assay
Mobility shift assays were performed as described by Barberis (11) with minor modifications. The binding activity was determined after incubation of 4 µg of nuclear protein extract with either 32P-labled 22-mer oligonucleotide encompassing the activator protein-1 (AP-1)–binding site (5'-CTAGTGATGAGTCAGCCGCATC-3'; Promega, Madison, WI) or nuclear factor (NF)-B–binding site (5'-AGTTGAGGGGACTTTCCCAGGC-3'; Promega).
BALF Total and Differential Cell Count and Tissue Histology
For more details see the online data supplement.
Total cell number was counted with hemocytometer from resuspended cell pellet (Hausser, Horsham, PA). BALF and paraformaldehyde-fixed lungs were stained with hematoxylin-eosin for qualitative cell count and histology. An experienced pathologist analyzed the lung tissues in a double-blind fashion.
Statistics
Results are presented as mean ± SD. Kruskal-Wallis test was performed for multiple group comparison, and intergroup differences were analyzed with Wilcoxon Rank Sum Test (22) with SPSS statistics software (SPSS, Chicago, IL). Significance level was p < 0.05.
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RESULTS
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Ventilation Enhances LPS-induced Lung Injury
To determine the magnitudes of lung injury caused by LPS, ventilation, and LPS/ventilation we performed 2-hour experiments. LPS animals were killed 2 hours after injection of LPS. In the LPS/ventilation condition, animals received LPS injection, were allowed to spontaneously breathe for 1hour, and then treated with 1 hour mechanical ventilation. Ventilation only animals received 2 hours of mechanical ventilation and were then killed. For all animals, we measured total cell number and total protein from the BALF. LPS or ventilation alone significantly augmented the total cell number measured in the lavage fluid, as did LPS followed by ventilation (Figure 1A). LPS treatment followed by ventilation also significantly enhanced the total protein levels in BALF, whereas ventilation or LPS alone did not increase BALF protein levels (Figure 1B). Figure 2 demonstrates the hematoxylin-eosin stained histology of the lung tissue after 2 hours of treatment. When compared with PBS treatment (Figure 2A), LPS or ventilation alone caused inflammatory cell infiltration into the alveolar septi and thickening of the alveolar wall (Figures 2B and 2C). The combined effect of LPS and ventilation was the most injurious that resulted in the destruction of the alveolar structure (Figure 2D). Greater magnification shows infiltrating mononuclear leucocytes into the alveoli (Figure 2E). The histology further supports the finding that ventilation further enhances LPS-induced lung injury.
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Figure 1. Effects of ventilation on BALF cell number and protein. (A) Total cell count showed significantly increased cell number after LPS, ventilation, and LPS/ventilation treatment (x104 cells/ml BALF). Values represent mean ± SD in all figures; n = 6 animals were used per condition. *Significant difference lps (p < 0.02), v (p < 0.029), and lps/v (p < 0.025) versus c. c = control animals were injected with PBS. After 1 hour trachesostomy was performed, and the animals were killed immediately. lps = LPS animals were LPS treated, after 1 hour tracheostomy was performed, and the animals were killed 1 hour after tracheostomy. v = ventilation animals were injected with PBS. After 1 hour tracheostomy was performed, and animals received 2 hours mechanical ventilation. lps/v = LPS/ventilation animals were LPS treated, after 1 hour tracheostomy was performed, and animals were mechanically ventilated for 1 hour. The same abbreviations are used for following figures. (B) Effects of ventilation on total protein measurement in the BALF supernatant (µg/ml). Only LPS/ventilation treatment increased significantly the level of total protein during the 2-hour period; n = 6 animals were used per condition. *Significant difference versus c (p < 0.01).
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Figure 2. Lung tissues were stained with hematoxylin-eosin to demonstrate the magnitude of lung injury (x40 magnification power). (A) Control. The alveoli and the capillaries are intact with no edema formation. (B) LPS treatment. The alveolar septi are thickened. Inflammatory cells are visible in the septi. The epithelial barrier is intact. (C) Ventilation. The alveolar septi are further thickened, partly ruptured, the inflammatory cell involvement in the septi is more characteristic. Red blood cells and edema fluid are present in the alveoli. (D) LPS/ventilation. The alveolar walls are ruptured and tissue is invaded by inflammatory cells. Red blood cells and edema fluid are present in the alveoli. (E) LPS/ventilation (x100 magnification power). The arrows point to mononuclear leukocytes in the alveoli. (F) LPS/ventilation/CO. CO treatment modestly reduced hypercellularity and inflammation in the tissue when compared with LPS/ventilation. (G) SB203580/LPS/ventilation/CO treatment resulted in hemorrhage and inflammatory response in the tissue. lps/v/co = LPS/ventilation/CO animals were LPS treated, after 1 hour tracheostomy was performed, and animals were mechanically ventilated with room air mixed with 250 ppm CO for 1 hour. SB203580/lps/v/co = SB203580/LPS/ventilation/CO animals were pretreated with SB203580. Subsequently animals were LPS treated, after 1 hour tracheostomy was performed, and animals were mechanically ventilated with room air mixed with 250 ppm CO for 1 hour. The same abbreviations are used for the following figures. Three animals per condition were used to prepare histology and representative one is displayed.
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Proinflammatory cytokine tumor necrosis factor- (TNF-) levels dramatically increased in BALF after LPS/ventilation treatment compared with the control or ventilation alone treatment conditions (Figure 3A). Kinetic experiments show significantly elevated TNF- levels in LPS/ventilation-treated animals after 30 minutes ventilation. The maximal TNF- level was measured after 1 hour ventilation on the 3-hour ventilation time course (Figure 3B).
VILI Induces HO-1 Expression
To examine whether VILI can induce expression of the stress-inducible HO-1, we performed Northern and Western blot analyses to determine HO-1 expression levels in the lung tissues after ventilation. As depicted in Figure 4, LPS or mechanical ventilation alone increased HO-1 gene and protein expression. The use of LPS, as a primer of lung injury, followed by ventilation increased HO-1 mRNA and protein expression the most when compared with control animals (Figures 4A and 4B). These data suggest that HO-1, an important cellular stress response gene product, may play a role in defense against VILI.
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Figure 4. HO-1 mRNA and protein expression after ventilation. (A) Northern blot analysis of lung tissue shows increased HO-1 mRNA expression LPS, ventilation (v), and LPS/ventilation treatment. 18S rRNA is included for RNA loading normalization. (B) LPS, ventilation, and LPS/ventilation treatment increased the HO-1 protein expression in the lung tissue. Coommassie staining of gel was used for protein loading normalization (data not shown). c = controls.
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Inhaled CO Inhalation Attenuates VILI
Inhaled CO significantly reduced the total cell number increased by LPS/ventilation in the BALF (Figure 5A). Ventilation alone with CO (ventilation/CO condition) markedly reduced the total cell number, but it did not reach significance. CO did not affect cell count in control and LPS treatment conditions (data is not shown). CO treatment did not affect the elevated total protein levels (Figure 5B).
We observed a dose-dependent decrease of the proinflammatory cytokine TNF- in BALF when the animals inhaled CO during mechanical ventilation (Figure 5C). We also measured the antiinflammatory cytokine interleukin-10 (IL-10) in the BALF. LPS, ventilation, or their combination did not affect IL-10 levels. CO treatment in LPS/ventilation/CO condition significantly increased IL-10 in the BALF. The effect was not observed in ventilation/CO condition (Figure 5D). CO did not have an effect on cytokine levels in control and LPS treatment conditions (data not shown). Modest decrease in hypercellularity and inflammation was observed in tissue histology after CO treatment (Figure 2F).
Differential cell count showed significantly reduced number of macrophages in the BALF after 2 hours of treatment with 250 ppm CO mixed with room air (Table 1). The number of neutrophil leukocytes in the BALF at this time point was negligible. To examine whether CO inhalation can effect neutrophil leukocyte infiltration to the alveoli, we performed LPS/ventilation and LPS/ventilation/CO condition experiments in which animals received LPS injection, were allowed to spontaneously breathe for 1 hour, and were then mechanically ventilated for 4 hours. Treatment with 250 ppm CO resulted in significantly reduced total cell count and neutrophil cell count in the BALF (Table 1). This finding suggests that CO may also reduce lung injury via inhibiting neutrophil leukocyte infiltration into the alveolar space.
Inhaled CO Exerts Negligible Effects on Hemodynamics and Oxygenation
To confirm that mechanical ventilation and low dose inhaled CO used for our studies did not exert untoward effects on hemodynamics and gas exchange, we measured blood pressure and blood gases in LPS/ventilation and LPS/ventilation/CO conditions. After tracheostomy, a cannula was inserted in the right carotid artery and blood pressure was continuously measured during the ventilation. Blood was sampled from the cannula for blood gases in the beginning and the end of mechanical ventilation. We did not observe statistically significant differences in blood pressure, pH, PCO2, and PO2 in LPS/ventilation and LPS/ventilation/CO conditions during the course of the experiment. Intergroup differences were not significant either. LPS treatment or ventilation alone had no effect on the hemodynamic of the animal model (data not shown). The carboxy-hemoglobin level was significantly elevated in CO-treated animals, as expected (Tables 2 and 3).
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TABLE 3. Blood gases and carboxy-hemoglobin before and after mechanical ventilation with and without carbon monoxide
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Mechanisms of CO-induced Antiinflammatory Effects
Transcription factors are involved in cellular stress–induced gene expression and regulate biological processes including inflammation, cell proliferation, and cell survival, all of which are important in conferring protection against cell and tissue injury (10). We examined whether transcription factors such as AP-1 and NF-B are involved in CO-induced antiinflammatory effects in VILI. LPS and ventilation both induced activation of AP-1 and NF-B (Figures 6A and 6B); however, CO treatment did not modulate the activation of AP-1– or NF-B–binding activity compared with ventilation or LPS/ventilation treatment.
Another intracellular pathway that is activated in lung injury is p38 mitogen-activated protein kinase (MAPK) (23). In our model LPS and ventilation increased activation of p38 MAPK; CO significantly increased p38 MAPK activation when compared with ventilation and LPS (Figure 7). To examine whether CO-induced p38 activation exerted biological effects, we measured the levels of the antiinflammatory molecule IL-10. We demonstrate that inhibition of p38 with the chemical inhibitor SB203580 compound significantly attenuates CO induced IL-10 levels (Figure 8) and histology shows hemorrhagic, inflamed lung tissue (Figure 2G).
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Figure 7. p38 mitogen-activated kinase (MAPK) activation in the lung tissue after CO treatment was detected by Western blotting. A specific phosphorylated p38 MAPK antibody was used. CO treatment (lps/v/co condition) significantly increased p38 MAPK protein expression. Total p38 MAPK is shown for protein loading control. c = controls.
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Figure 8. SB203580 p38 MAPK inhibitor attenuated IL-10 levels in the BALF. When animals were treated according to SB203580/LPS/ventilation/CO condition, IL-10 BALF levels were significantly lower than after LPS/ventilation/CO treatment; n = 6 animals were used/condition. *Significant increase in IL-10 levels lps/v/co versus c (p < 0.01).  Significant difference between of lps/v/co versus SB203580lps/v/co (p < 0.038). c = controls.
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DISCUSSION
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Preclinical animal models of VILI have shown that the inflammatory milieu of pro- and antiinflammatory cytokines plays a significant role in the pathology of VILI by causing biotrauma (7, 11, 22). It is speculated that cytokines released from the inflamed lungs to the blood may further cause deleterious physiologic effect on the host by injuring other organs, precipitating multiple organ failure (24).
We used a relatively injurious VILI model in rats, which resulted in lung injury that features inflammation, and edema as assessed by cell count, TNF- production, and protein in the BALF (25, 26). We performed TUNEL assay in our lung tissues and did not observe evidence of cell death after VILI (data not shown). To better mimic a human disease course and maximize VILI, we used a sublethal dose of LPS to prime and supplement VILI, as often used by investigators (7, 9). Other injurious caustic agents such as hydrochloric acid or oleic acid were also applied to prime VILI in rodents (11, 27). Because it has been suggested that high volume ventilation may also affect hemodynamics (8), we measured blood gas and arterial blood pressure parameters and did not observe significant changes in blood pH, PCO2, PO2, and arterial blood pressure.
We initially observed a robust induction of HO-1 mRNA and protein in this model of VILI. Our laboratory and others have shown that HO-1 induction in response to cellular and tissue stress, in vitro or in vivo, is not only a reliable marker of cellular injury but also a physiologic response to defend against the inciting stress or cellular insult. Recently, our laboratory has provided evidence that CO, a major by-product of heme catalysis by HO-1, mediates the protective effect of HO-1 (15–19). Thus, in view of our observation that HO-1 was markedly increased in VILI, we sought to assess whether CO could be responsible in mitigating VILI.
Using the same concentration of CO (250 ppm) we have used previously for in vitro and in vivo studies, we observed that CO could markedly attenuate the inflammatory responses of VILI. Inhaled CO significantly reduced the BALF cell count and TNF- levels. Interestingly, we also observed that CO increased levels of the antiinflammatory IL-10 in the BALF. These results correlate with the previous observations of Otterbein and colleagues in mice and murine macrophages (18).
Macrophages are the principal cell type found in the BALF after LPS/ventilation treatment. Macrophages are known to be sensitive to mechanical stress; thus, the changes in BALF total cell count might reflect an important role of macrophages in cytokine release in VILI (28). Belperio and colleagues described neutrophil leukocyte–predominant inflammatory response in mice after 6 hours high-volume (12 ml/kg) mechanical ventilation (29). In our model, neutrophil leukocyte infiltration to the alveolar space was observed after 4 hours of mechanical ventilation. Inhaled CO significantly reduced neutrophil recruitment to the alveoli. Additionally, inhaled CO also reduced BALF macrophage numbers at 2 hours. TNF- is a well known and well investigated cytokine that has a proinflammatory effect in in vivo and in vitro models (10, 30), and IL-10 has antiinflammatory activity in LPS-induced inflammation (31). It is interesting to note that CO did not affect the BALF protein levels, suggesting that CO exerts negligible effects on pulmonary permeability. This observation provides us additional clue as to the differential and specific antiinflammatory effects of CO, which at this time appears to act as a regulator of inflammation by attenuating proinflammatory cytokines and augmenting antiinflammatory cytokines.
The signaling pathway by which CO acts as an antiinflammatory agent is not fully understood. Although it is well established that CO activation of soluble guanylyl cyclase and cGMP mediates much of the vasodilatory effects (32), we did not observe a cGMP-dependent effect in our VILI model (data not shown). Recent evidence suggests that pathways independent of cGMP are important in mediating CO signaling pathways. These cGMP-independent pathways include the ERK MAPK in airway smooth muscle cell proliferation (33), p38- MAPK and Egr-1 pathways in ischemia-reperfusion lung injury (34, 35), AP-1 in murine macrophages in response to LPS, and the p21 and p38 MAPK pathway in vascular smooth muscle cell proliferation (19, 36). We showed that NF-B and AP-1 activation, two major pathways in VILI (7, 10), are not modulated by CO inhalation in VILI. The p38 MAPK is known to regulate TNF- and IL-10 (37, 38) production. Although the molecular mechanism by which CO affects p38 MAPK to produce less TNF- and more IL-10 needs to be further investigated, CO may have a posttranscriptional effect on TNF- production (38).
We believe that our model can lead to a better understanding of the complex intracellular regulatory function of CO in lung injury. Based on the observations of this study, it is tempting to speculate that inhaled CO could represent a potential new therapeutic modality for counteracting VILI.
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Acknowledgments
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The authors thank W. Ameredes for his technical assistance and T. Oury for the evaluation of histology.
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FOOTNOTES
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Supported by grants RO1 HL-55330 and HL-60234 from the National Institutes of Health, by the European Respiratory Society Short-Term Research Fellowship, by the Hungarian Respiratory Society Research Fellowship, and by the Joseph Eötvös Public Foundation Scholarship.
This article has an online data supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Conflict of Interest Statement: T.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.M.K.C. has received investigator-driven research grant from AGA-Linde providing $100,000 to cover the cost of equipment involved in inhalation of CO and a research technician during the 1-year duration of the industry-sponsored research grant, and has received a $4,500 fee for an investigator meeting organized by AGA-Linde and consultation for CO research.
Received in original form January 7, 2004;
accepted in final form May 7, 2004
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ABSTRACT
METHODS
Significant increase of TNF-
