Interferon-
: a key contributor to hyperoxia-induced lung injury in mice
Mitsuhiro Yamada,
Hiroshi Kubo,
Seiichi Kobayashi,
Kota Ishizawa, and
Hidetada Sasaki
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Miyagi, Japan 980-8574
Submitted 30 April 2004
; accepted in final form 15 July 2004
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ABSTRACT
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Hyperoxia-induced lung injury complicates the care of many critically ill patients who receive supplemental oxygen therapy. Hyperoxic injury to lung tissues is mediated by reactive oxygen species, inflammatory cell activation, and release of cytotoxic cytokines. IFN-
is known to be induced in lungs exposed to high concentrations of oxygen; however, its contribution to hyperoxia-induced lung injury remains unclear. To determine whether IFN-
contributes to hyperoxia-induced lung injury, we first used anti-mouse IFN-
antibody to blockade IFN-
activity. Administration of anti-mouse IFN-
antibody inhibited hyperoxia-induced increases in pulmonary alveolar permeability and neutrophil migration into lung air spaces. To confirm that IFN-
contributes to hyperoxic lung injury, we then simultaneously exposed IFN-
-deficient (IFN-
/) mice and wild-type mice to hyperoxia. In the early phase of hyperoxia, permeability changes and neutrophil migration were significantly reduced in IFN-
/ mice compared with wild-type mice, although the differences in permeability changes and neutrophil migration between IFN-
/ mice and wild-type mice were not significant in the late phase of hyperoxia. The concentrations of IL-12 and IL-18, two cytokines that play a role in IFN-
induction, significantly increased in bronchoalveolar lavage fluid after exposure to hyperoxia in both IFN-
/ mice and wild-type mice, suggesting that hyperoxia initiates upstream events that result in IFN-
production. Although there was no significant difference in overall survival, IFN-
/ mice had a better early survival rate than did the wild-type mice. Therefore, these data strongly suggest that IFN-
is a key molecular contributor to hyperoxia-induced lung injury.
neutrophils; inflammation; oxygen toxicity; cytokines; acute lung injury
PATIENTS WITH RESPIRATORY FAILURE are commonly given supplemental oxygen to maintain tissue oxygen tension. Pulmonary oxygen toxicity, however, is an important clinical problem in these patients. Adult animals, including humans, develop acute lung injury when they breathe very high inspired oxygen fractions for a period of time (1, 3, 19). Oxygen-induced lung injury is characterized by increasing damage to alveolar-capillary membranes, resulting in apoptosis of the alveolar endothelium and epithelium (1). Because many patients require oxygen therapy to survive critical illnesses or injuries, pulmonary oxygen toxicity and its prevention are significant clinical issues.
The pathogenesis of hyperoxia-induced lung injury is not completely understood but is believed to be mediated by direct cell damage via the generation of reactive oxygen species (ROS) (8, 10, 15, 26). However, proinflammatory cytokines such as TNF-
and IFN-
may also play an important role in causing injury. Recent studies have detected increased concentrations of TNF-
and IFN-
in lungs exposed to hyperoxia before any neutrophil infiltration was evident (12, 25). Another study showed that mice lacking TNF receptor, TNF receptor I, or TNF receptor II remained susceptible to hyperoxia (21), suggesting that TNF-
is not the key molecule for hyperoxia-induced lung injury.
IFN-
is known to be released from lung cells, including pulmonary lymphocytes, after exposure to hyperoxia (25). Several studies have shown that IFN-
induces apoptosis in several cell types, including lung epithelial cells, and is known to mediate lung injury (4, 14, 27, 28, 30, 32). In addition, studies using IFN-
-deficient (IFN-
/) mice reported that IFN-
plays a role in pulmonary inflammation (2, 24). However, the role of IFN-
in hyperoxia-induced acute lung injury and inflammation needs further elucidation. In the current study, experiments involving anti-mouse IFN-
antibody and IFN-
/ mice were carried out to determine whether IFN-
contributes to hyperoxia-induced lung injury.
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MATERIALS AND METHODS
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Animals.
IFN-
/ mice (C57BL/6 background) were purchased from Jackson Laboratories (Bar Harbor, ME). Wild-type (WT) C57BL/6 mice were purchased from CLEA Japan (Tokyo, Japan). All mice were 7- to 8-wk-old males and were housed in specific pathogen-free conditions for 1 wk before experimental use. All experiments were performed in accordance with the Animal Studies Committee regulations of the Tohoku University School of Medicine.
Treatment with antibodies to IFN-
.
ALZET osmotic pumps (ALZA, Palo Alto, CA) were used to administer antibodies to the study animals. The pumps were filled with either goat anti-mouse IFN-
antibody (Genzyme-Techne, Cambridge, MA) dissolved in sterilized phosphate-buffered saline (PBS) or control antibody consisting of isotype-matched normal goat IgG (Genzyme-Techne). Antibody was infused at a rate of 140 ng/h (total of 10 µg/mouse). This amount of anti-mouse IFN-
antibody is enough to neutralize 1 ng of recombinant murine IFN-
according to the manufacturer's instructions. The pumps were implanted subcutaneously 24 h before exposure to hyperoxia.
Oxygen exposure.
Mice were exposed to hyperoxic conditions by delivery of 100% oxygen at 3 l/min to a 50 x 30 x 30-cm airtight chamber. The fractional concentration of inspired O2 in the chamber was continuously monitored with an oxygen analyzer (TAIEI Electronics, Kasama, Japan) and maintained at 9899% during the exposure. The chamber bottom was lined with a CO2 absorbant(Sodalime; Wako, Tokyo, Japan) to remove CO2 that was produced by the mice. The chamber was provided with a fan to circulate the inner air to remove CO2 efficiently by a CO2 absorbant. We checked the CO2 level in the chamber every 24 h during the experiment using a gas analyzer (ABL 700; Radiometer, Copenhagen, Denmark) and confirmed that the CO2 level was held <0.5%. The mice were given free access to food and water and were exposed to a 12-h light-dark cycle.
Bronchoalveolar lavage.
Mice were killed by an overdose of halothane, and then lavage tubes were implanted into the mice according to the following procedure: a median sternotomy was performed, the trachea was dissected free from the underlying soft tissues, and a 0.8-mm lavage tube was inserted through a small incision in the trachea. We performed bronchoalveolar lavage (BAL) by instilling 0.5 ml of ice-cold PBS into the lungs and then gently aspirating the fluid. BAL was repeated two times with fresh 0.5-ml aliquots of PBS. These three fluid samples were pooled and centrifuged. Cell counts and differentials were performed. Cell-free BAL fluid was stored at 80°C until assayed.
Measurements of protein, IFN-
, IL-12 p70, and IL-18 in BAL fluid.
BAL protein in cell-free BAL fluid was assayed as an index of lung injury and capillary leakage. Protein quantification was accomplished with the BCA Protein Assay Reagent Kit (Pierce Biotechnology, Rockford, IL). Concentrations of murine IFN-
, IL-12 p70, and IL-18 in cell-free BAL fluid were measured with commercial enzyme-linked immunosorbent assay kits. The enzyme-linked immunosorbent assay kits for murine IFN-
and murine IL-12 p70 were purchased from Amersham Pharmacia Biotech (Piscataway, NJ). The enzyme-linked immunosorbent assay kit for murine IL-18 was purchased from Medical & Biological Laboratories (Nagoya, Japan).
Statistical analysis.
Data are expressed as the means ± SE. Statistical analysis was performed on a Macintosh computer system with Statview 4.0 statistical analysis software (SAS Institute, Cary, NC). Normally distributed data were assessed for significance by ANOVA followed by the Bonferroni-Dunn method for multiple comparisons. Differences in survival between IFN-
/ and WT mice were assessed by the Kaplan-Meier method with the Mantel-Cox log rank test. A difference was considered statistically significant at P < 0.05.
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RESULTS
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In vivo neutralization of IFN-
inhibited neutrophil migration into the lung air space and inhibited increases in pulmonary alveolar permeability after exposure to hyperoxia.
To investigate whether IFN-
contributed to hyperoxia-induced lung injury, we first used anti-mouse IFN-
antibody to blockade IFN-
activity. BAL total cell counts and neutrophil counts were measured in C57BL/6 mice treated with an anti-IFN-
antibody or control IgG after a 48-h exposure to normoxia or hyperoxia. After exposure to normoxia, similar levels of BAL cellularity were seen in both groups of mice (Fig. 1, A and B). After exposure to hyperoxia, the total cell count and the neutrophil count were significantly increased in the mice treated with a control IgG compared with the mice treated with control IgG after exposure to normoxia (Fig. 1, A and B). However, the mice treated with a neutralizing antibody to IFN-
registered no increase in the total cell count or in the neutrophil count in response to hyperoxia (Fig. 1, A and B). We also compared the BAL protein concentrations as a marker of pulmonary alveolar permeability changes. The concentration of total BAL protein significantly increased in the mice treated with control IgG after exposure to hyperoxia, compared with the mice exposed to normoxia, but did not significantly increase in the mice treated with a neutralizing antibody to IFN-
after exposure to hyperoxia (Fig. 1C). These data suggest that neutralization of IFN-
inhibited cellular accumulation, especially neutrophil accumulation, in the lung air space and also inhibited hyperoxia-induced increases in pulmonary alveolar permeability.
Significant reduction of neutrophil migration into the lung air space and inhibition of increases in pulmonary alveolar permeability after exposure to hyperoxia in IFN-
/ mice.
To further confirm the role of IFN-
in hyperoxic lung injury, we conducted a set of experiments using IFN-
/ mice. We compared the BAL total cell counts and neutrophil counts of C57BL/6 WT mice and IFN-
/ mice after a 48-h exposure to normoxia or hyperoxia. Total cell counts and neutrophil counts did not differ between WT and IFN-
/ mice after 48 h of normoxia (Fig. 2, A and B). After exposure to hyperoxia, the total cell count and the neutrophil count significantly increased in WT mice compared with the normoxia-exposed WT mice (Fig. 2, A and B). In contrast, although the total cell count and the neutrophil count did increase in IFN-
/ mice after exposure to hyperoxia, this increase was significantly less than the increases observed in the WT mice exposed to normoxia (Fig. 2, A and B). We also compared BAL total protein concentrations in WT and IFN-
/ mice. After exposure to normoxia, the concentrations of BAL protein were similar in both groups (Fig. 2C). The concentration of BAL protein significantly increased in the WT mice exposed to hyperoxia for 48 h compared with WT mice exposed to normoxia. However, whereas BAL protein also increased in IFN-
/ mice after exposure to hyperoxia, this increase was significantly less than the increase observed in the WT mice exposed to hyperoxia (Fig. 2C). We also examined BAL total cell counts, BAL neutrophil counts, and BAL protein concentrations in C57BL/6 WT mice and IFN-
/ mice after 72 and 84 h to assess how IFN-
contributes to hyperoxia-induced lung injury in the late phase as well as in the early phase. As shown in Fig. 3, the total cell count, the neutrophil count, and the BAL total protein concentration were significantly decreased in IFN-
/ mice compared with the WT mice at 48 and 72 h. However, after 84 h of exposure, differences in the total cell count, the neutrophil count, and the BAL total protein concentration between WT and IFN-
/ mice were no longer significant (Fig. 3). These data suggest that IFN-
plays a more important role in the early phase of hyperoxic lung injury (within 72 h), especially with respect to neutrophil accumulation in the lung air space and hyperoxia-induced increases in pulmonary alveolar permeability.
Production of IFN-
and IFN-
-associated cytokines in response to hyperoxic exposure.
Exposure to hyperoxia increased the concentration of IFN-
in BAL fluid in WT mice (Fig. 4A). IFN-
was basically undetectable in IFN-
/ mice, even after exposure to hyperoxia (Fig. 4A). Production of IFN-
is promoted by cytokines such as IL-12 and IL-18 that are produced by antigen presenting cells. We thus also investigated whether IL-12 or IL-18 concentrations were increased in BAL fluid after exposure to hyperoxia in both IFN-
/ mice and WT mice. After 48 h of exposure to hyperoxia, IL-12 and IL-18 concentrations in BAL fluid were significantly elevated in both IFN-
/ mice and WT mice compared with mice exposed to normoxia (Fig. 4). There was no difference in IL-12 and IL-18 concentrations between WT and IFN-
/ mice after 48 h of hyperoxia exposure (Fig. 4). At 24 h, although IFN-
, IL-12, and IL-18 concentrations had all begun to rise, only the elevation in IL-12 concentration was significant (Fig. 5).
Survival of IFN-
/ mice in hyperoxia.
Our data suggested that IFN-
plays an important role in hyperoxia-induced lung injury. To determine the importance of IFN-
in oxygen-induced mortality, the survival of IFN-
/ mice and WT mice exposed simultaneously to hyperoxia was compared. As demonstrated in Fig. 6A, there was no significant difference in overall survival between IFN-
/ mice and WT mice (P = 0.1304 by Mantel-Cox log rank test). The average time of death for WT mice was 93.5 ± 4.4 (SE) h (range 72120 h) compared with 105 ± 3.6 h (range 78120 h) for IFN-
/ mice. Analysis of the natural log cumulative hazard plot (Fig. 6B), which evaluates the natural log of the cumulative hazard as a function of the natural log of the time of death and thereby allows an estimation of relative hazard of each strain over time, suggests that the IFN-
/ mice had a better early survival rate than did the WT mice.
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DISCUSSION
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Hyperoxia induces massive pulmonary damage, resulting in pulmonary edema, poor gas exchange, and respiratory failure. In this study, we demonstrated that IFN-
contributes to hyperoxia-induced lung injury, including neutrophil accumulation in murine lungs. Hyperoxia-induced lung injury is believed to result from the direct toxic effects of ROS as well as from indirect effects of inflammatory cell activation and the resultant synthesis of cytokines. The current study confirmed previously reported findings that the concentration of IFN-
significantly increased in BAL fluid in mice within 4872 h of exposure to hyperoxia (25). However, the current study also found that inhibiting IFN-
by an anti-IFN-
antibody or gene knockout attenuated hyperoxia-induced neutrophil accumulation and lung injury. Because oxygen toxicity affects many cell types in the lung, it has been difficult to determine precisely which cell types or which mediators are involved in causing hyperoxia-induced lung injury. Our data clearly demonstrate that IFN-
played an important role in the early phase of hyperoxia-induced lung injury.
A previous study showed that IFN-
was produced by pulmonary lymphocytes in hyperoxia-exposed mice (25). IFN-
is the major effector cytokine produced by type 1 CD4+ and CD8+ T cells and natural killer cells. Early release of IFN-
from type 1 CD4+ and CD8+ T cells in the lung could theoretically occur either after local activation or after systemic activation followed by migration of these preactivated T cells into the lung. Our data show that depletion of IFN-
attenuated neutrophil accumulation in the lung air space and also inhibited hyperoxia-induced increases in pulmonary alveolar permeability in the early phase of hyperoxic injury. In fact, since IFN-
leads to upregulation of adhesion molecule expression (7, 23, 31), a reasonable conclusion from these experiments is that neutrophil infiltration into lungs exposed to hyperoxia is itself due to increased production of IFN-
. Although neutrophil migration into lungs exposed to hyperoxia is independent of the CD11/CD18 adhesion complex (6, 13), IFN-
might contribute to upregulation of other neutrophil-endothelial adhesion molecules. In the late phase of hyperoxia-induced lung injury, no differences in neutrophil accumulation and hyperoxia-induced increases in pulmonary alveolar permeability were observed between the BAL fluids from WT and IFN-
/ mice. Consequently, the study results indicate that neutrophil accumulation in the late phase of hyperoxia-induced lung injury did not depend on IFN-
; rather, late-phase neutrophil accumulation might be caused by a reaction to apoptosis or to necrosis of lung epithelium caused by ROS.
We observed that the hyperoxia-induced neutrophil accumulation was completely blocked in the mice with the IFN-
neutralizing antibody, which appeared significant in IFN-
/ mice though lower than that in controls. To explain this discrepancy, several hypotheses can be considered: 1) mice chronically deficient in IFN-
may induce alternative adhesion pathways or chemokines for neutrophil accumulation induced by hyperoxia; or 2) neutralizing IFN-
by antibody may have another inhibitory effect on hyperoxia-induced injury through mechanisms other than simply IFN-
blockade. This kind of discrepancy in the observed function of molecule when evaluated using neutralizing antibody compared with gene knockout has been reported in several experimental models (5, 22). An alternative pathway that is utilized in mutant mice was also reported (16). However, our data do not allow us to clear this discrepancy. Further examinations are needed.
Consistent with an upregulation of IFN-
expression in BAL fluid, IL-12 and IL-18 were also found to be upregulated in BAL fluid within 48 h of exposure to hyperoxia. Because IFN-
production is potently enhanced by IL-12 (11) and Il-18 (18), the presence of IL-12 and IL-18 upregulation in BAL fluids is noteworthy. The observation that IL-12 was upregulated in BAL fluid within 24 h before the upregulation of IFN-
suggests that IL-12 may contribute to IFN-
production in these hyperoxia-induced inflammatory responses, although further examinations, for example, using IL-12 blocking antibody or IL-12-deficient mice, need to be done to determine whether IL-12 stimulates or regulates the production of IFN-
. In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play a critical role in the host defense against infection with intracellular microbes through the induction of IFN-
. However, overproduction of IL-12 and IL-18 induces severe inflammatory disorders, suggesting that IL-12 and IL-18 are potent proinflammatory cytokines that have pathophysiological roles in several inflammatory conditions. Therefore, IL-12 and IL-18 may contribute to hyperoxia-induced lung injury via the upregulation of IFN-
, resulting in neutrophil migration into the lungs.
In the current study, although the early survival of the IFN-
/ mice was improved compared with WT mice, there was no significant difference in the overall survival between IFN-
/ mice and WT mice. These results reflect the observation that the early phase of hyperoxia-induced lung injury depends on proinflammatory cytokines produced by inflammatory cells. In contrast, the late phase of this lung injury depends more on the effects of direct injury by ROS rather than on the effects of inflammatory processes. In fact, mouse models associated with improvements in overall survival contain transgenic enzymes and cytokines that upregulate the ability of the mice to remove ROS (8, 20, 29). However, in practice, many critically ill patients are supported with high doses of oxygen for no more than 72 h. Therefore, understanding and inhibiting early-phase mechanisms of injury would appear to be clinically important in minimizing hyperoxia-induced lung injury. Our results showed that depletion of IFN-
attenuated hyperoxia-induced lung injury. Blockade of the function of proinflammatory cytokines, such as IFN-
, IL-12, and IL-18, may thus prove to be an effective method for preventing early-phase hyperoxia-induced lung injury.
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GRANTS
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This work was supported by Japan Society for the Promotion of Science Grant 13670589 to H. Kubo.
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ACKNOWLEDGMENTS
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We thank Prof. Claire M. Doerschuk (Department of Pediatrics, Case Western Reserve University) for discussions and technical advice.
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FOOTNOTES
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Address for reprint requests and other correspondence: H. Kubo, Dept. of Geriatric and Respiratory Medicine, Tohoku Univ. School of Medicine, 1-1 Seiryoumachi, Aobaku, Sendai 980-8574, Japan (E-mail: hkubo{at}geriat.med.tohoku.ac.jp)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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