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*
National Institutes of Health Asthma and Allergic Diseases Research Center and Department of Internal Medicine and
Department Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX 77555
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and macrophage-inflammatory protein-2), CXCL10
(IFN-
-inducible protein-10), CCL3 (macrophage-inflammatory
protein-1), CCL7 (monocyte chemoattractant protein-3), and
CCL11 (eotaxin) at 0 h postexposure, and expression of CXCL10,
CCL3, and CCL7 mRNA was sustained 18 h postexposure.
O3 increased lung protein levels of CXCL10, CCL7, and CCR3
(CCL7R). The airway epithelium was identified as a source of CCL7. The
role of up-regulated chemokines was determined by administering control
IgG or IgG Abs against six murine chemokines before O3
exposure. As expected, anti-mouse growth-related oncogene-
inhibited neutrophil recruitment. Surprisingly, Abs to CCL7 and CXCL10
also decreased neutrophil recruitment by 63 and 72%, respectively.
These findings indicate that CCL7 and CXCL10, two chemokines not
previously reported to orchestrate neutrophilic inflammation, play a
critical role in mediating oxidative stress-induced neutrophilic airway
inflammation. These observations may have relevance in induction of
neutrophilia in severe asthma. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Oxidative injury from O3 exposure has been shown to induce recruitment of neutrophils and decrement in lung function in patients with asthma (7, 8). Likewise, animal studies have demonstrated that O3 exposure potently induces recruitment and activation of neutrophils in the airways (9, 10, 11, 12). Activation of neutrophils is likely to produce additional damage through the release of reactive oxygen species and proteolytic enzymes (7). We and others have shown that airway neutrophilia in asthma is associated with sudden onset fatality, severe asthma, and peribronchial fibrosis (13, 14, 15, 16, 17, 18). These studies suggest that neutrophils may play an important role in severe asthma and support the concept that O3 oxidative stress-induced recruitment and activation of neutrophils may contribute to exacerbation of asthma.
Chemokines belong to a family of cytokines responsible for attracting inflammatory leukocytes, and some chemokines have been shown to be up-regulated in the lungs upon O3 exposure. Earlier studies have reported that O3 up-regulates CXCL-8 mRNA expression and protein production in the lungs of animals and humans exposed to O3 (19, 20). In addition to CXCL-8, O3 has been shown to induce other CXC chemokines, such as members of the Gro family of CXCL1,2,3 and CXCL10 (21, 22, 23). Other investigators have reported that O3 up-regulates CC chemokines such as CCL2, CCL3, and CCL11 (21, 23). Even though O3 exposure has been shown to up-regulate these chemokines, few studies have evaluated the in vivo role of these chemokines, which mediate O3-induced airway inflammation (12). The present study was designed to identify CC and CXC chemokines that have not been previously reported to mediate O3-induced airway inflammation. Here, we show that CCL7 and CXCL10, two chemokines not reported to mediate neutrophilic inflammation, orchestrate oxidative stress-induced neutrophilic airway inflammation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six- to 8-wk-old BALB/c mice (Harlan Laboratories, Indianapolis,
IN) were placed in individual stainless steel wire-mesh cages with free
access to food and water and were exposed to either sham air or
O3 using Hinners-type
0.85-m3 stainless steel chambers. The inlet air
was passed through activated charcoal and HEPA filters at sufficient
flow to achieve chamber turnover rates of 30 volume changes/h.
O3 was generated from 100%
O2 (medical grade) using a silent arc electrode
(Sander, Uetze-Eltze, Germany) adjusted to achieve the desired
chamber O3 concentration. The total
O3/O2 flow was introduced
into the chamber-input port using mass flow controllers (Scott
Specialty Gas, Pasadena, TX) to tightly regulate the flow of
O2 through the ozonizer. Chamber temperature
(24.3 ± 0.4°C) and humidity (59.1 ± 1.7%) were
maintained in both sham air and O3 chambers
throughout the exposure period. O3 concentrations
were continuously monitored using a model 49 O3
analyzer (Thermo Environmental Instruments, Franklin, MD). Mice were
exposed for 6 h to either a low (0.2 ± 0.03 ppm) or high
(0.8 ± 0.03 ppm) dose of O3. After
exposure, sham and O3 exposed animals were
sacrificed, and bronchoalveolar lavage
(BAL)4 was performed
at 0, 18, 42, and 138 h after exposure cessation (Fig. 1
).
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Cellular infiltration into the airway lumen was assessed by an analysis of BAL fluid. Mice were anesthetized with an i.p. injection of ketamine and xylazine. A tracheotomy was performed and the trachea was cannulated. BAL of both lungs was performed twice with 0.7 ml of sterile PBS (pH 7.3) through the trachea cannula with a syringe. The BAL was centrifuged at 4°C for 10 min at 400 x g, and the pellet was suspended in 750 µl of ice-cold Dulbecco’s PBS (Sigma-Aldrich, St. Louis, MO). Total cell counts in BAL were determined from an aliquot of the cell suspension. Differential cell counts were done on cytocentrifuge preparations (Cytospin 3; Thermo Shandon, Pittsburgh, PA) stained with Wright-Giemsa, counting 200 cells from each animal.
Analyses of lung chemokine mRNA levels by RT-PCR
Chemokine mRNAs were assessed by semiquantitative RT-PCR.
Immediately after the mice were sacrificed, the lungs were removed,
frozen rapidly in liquid nitrogen, and stored at 80°C until RNA
extraction. The frozen whole lung was placed into 2 ml of TRIzol
solution (Life Technologies, Grand Island, NY) and homogenized using a
Polytron homogenizer. Total RNA was isolated following the
manufacturer’s protocol. Five micrograms of total RNA was reverse
transcribed using 200 U of SuperScript II Reverse Transcriptase in a
buffer (Life Technologies) containing 10 mM DTT, 1 µM oligo(dT)
primer (Life Technologies), 500 µM of each dNTP, and 10 U of RNasin
(Promega, Madison, WI) in a total volume of 20 µl. The resultant cDNA
was diluted 5-fold with diethyl pyrocarbonate-treated water to a final
volume of 100 µl. To amplify the reverse-transcribed cDNA, 4.0 µl
of the PCR mixture was added to give a final solution containing 1x
Taq buffer II, 2.0 mM MgCl2, 0.2 µM
of each sense and antisense primer, and 0.5 U of AmpliTaq Gold
polymerase (PerkinElmer/Applied Biosystems, Foster City, CA). PCR was
performed in GeneAmp PCR system 9700 (PerkinElmer/Applied Biosystems).
All primers were custom-designated using the Primer software program
(Table I). The number of amplification
cycles used ranged from 23 to 26. The number of amplification cycles
was selected for each primer based on the linear portion of the PCR
amplification cycle. The PCR products were electrophoresed in a 3%
agarose gel (Seakem LE Agarose; FMC Bioproducts, Riceland, ME). The
intensity of bands on photographs of the agarose gel was quantified by
scanning the photographs with a contrast scanner (JX-330; Sharp
Electronics, Mahwah, NJ) using optical software (ImageQuant, version
3.3; Molecular Dynamics, Sunnyvale, CA). The values obtained from
individual cytokines were expressed as a ratio of cytokine band
intensity relative to band intensity of housekeeping gene,
2-microglobulin
(2m).
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-inducible protein (IP)-10), CCL7 (monocyte
chemoattractant protein (MCP)-3), and CCR3 protein levelsWhole lung lysates of mice exposed to sham air or 0.8 ppm O3 for 6 h were subjected to denaturing gel electrophoresis. To detect these chemokines or chemokine receptors, Western blotting was performed using rabbit anti-murine chemokine Abs (PeproTech, Rocky Hill, NJ) or rabbit anti-murine CCR3 Ab (BD PharMingen, San Diego, CA).
Immunohistochemistry of lung sections for CCL7
Mice were exposed to either air or 0.8 ppm O3 for 6 h and the lungs were dissected out 18 h postexposure. Cryosections of the lung were fixed in methanol:acetone and blocked with goat serum. Serial sections of the lungs were incubated with either normal rabbit IgG or rabbit anti-mouse CCL7 (PeproTech, Rocky Hill, NJ). The tissue-bound anti-CCL7 was detected with Alexa 488-conjugated, highly cross-absorbed goat anti-rabbit IgG (Molecular Probes, Eugene, OR). The sections were visualized in an inverted TE200 Nikon Fluorecent microscope attached to a Photometrics Cool Snap Fx CCD digital camera and Metamorph software (Roper Scientific, Tucson, AZ).
Administration of anti-chemokine Abs
Rabbit IgG (control) and rabbit IgG Abs against CXCL1,2,3 (mouse
growth-related oncogene- (KC), macrophage-inflammatory
protein (MIP)-2), CXCL10 (IP-10), CCL3 (MIP-1), CCL7 (MCP-3), and
CCL11 (eotaxin) (PeproTech) were administered to naive BALB/c. All Abs
were administered intranasally (i.n.) at a concentration of 10 µg/100
µl PBS 1 h before O3 exposure (Fig. 1
B). We and others have previously shown that
anti-chemokine Abs are very effective in preventing lung
inflammation in vivo when they are administered directly into the lungs
(24, 25). For this reason, we administered Abs (rabbit
polyclonal IgG) directly into the lungs in this study. The mice were
exposed to 0.8 ppm O3 for 6 h and were
sacrificed to perform BAL at the anticipated peak of lung inflammation,
that is 18 h after the end of O3
exposure.
Specificity of rabbit anti-murine chemokine Abs
To determine specificity of rabbit anti-mouse chemokine Abs, we performed denaturing gel electrophoresis of recombinant murine CXCL10 (IP-10), KC, CCL7 (MCP-3), and CCL5 (RANTES), followed by Western blotting using rabbit Abs directed against murine CXCL10, KC, and CCL7 (PeproTech).
Data analysis
Data are presented as mean ± SEM. The difference in outcome variables between treatment groups was analyzed by one-way ANOVA. Significant ANOVAs were further analyzed by the Bonferroni/Dunn’s post hoc test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sham air exposure of BALB/c mice did not alter the number of
neutrophils, eosinophils, macrophages, or lymphocytes in the recovered
BAL at any time. Exposure of mice to a low concentration (0.2 ppm) of
O3 failed to induce a detectable increase in any
of these cell populations within the lungs. In contrast, exposure of
mice to a high concentration of O3 (0.8 ppm)
increased the total cells maximally by 18 h (air = 2.57
± 0.53 x 104/ml vs 0.8 ppm
O3 = 23.43 ± 4.99 x
104/ml; p 
0.01; Fig. 2). The same high concentration of
O3 increased the number of neutrophils at 18
h from 0.02 ± 0.0 x 104/ml in the air
control group to 9.44 ± 2.30 x 104/ml
(p 0.01, Fig. 2). Furthermore, 0.8 ppm
O3 also increased the number of macrophages at
18 h (air = 2.52 ± 0.52 x
104/ml vs 0.8 ppm O3 =
13.77 ± 3.37 x 104/ml;
p 0.01; Fig. 2). These data indicate that 0.8 ppm
O3 for 6 h increased total cells,
neutrophils, and macrophages as early as 18 h postexposure, and
both cell types demonstrated sustained increase until 42 h
postexposure.
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RT-PCR of lung mRNA was performed to measure expression of CXC and
CC chemokines, and the data of two representative chemokines, namely,
CXCL10 and CCL7, are shown in Fig. 3. The
ratio of intensity of chemokine band to the intensity of the
housekeeping gene 2m was determined (Fig. 4). Exposure of mice to 0.8 ppm
O3 for 6 h up-regulated some chemokine genes
at 0 h postexposure, which did not persist at 18 h
postexposure. These include the CXCL1,2,3 (KC, 10.5-fold increase,
p 0.001), MIP-2 (18.3-fold increase,
p 0.001), and CCL11 (9.1-fold increase,
p 0.01). Exposure of mice to the same dose of
O3 for 6 h up-regulated other genes at
0 h postexposure, but these genes remained up-regulated at 18
h postexposure. This group of chemokines includes CXCL10 (10.6-fold
increase, p 0.01), CCL3 (3.9-fold increase,
p 0.05), and CCL7 (13.1-fold increase,
p 0.0001). The expression of the second group of
chemokine genes (CXCL10, CCL3, and CCL7) was up-regulated 3.3-, 2.1-,
and 4.5-fold, respectively, at 18 h. These results indicate that
some genes (CXCL1,2,3 and CCL11) are only transiently up-regulated by
O3 exposure, whereas others (CXCL10, CCL3, and
CCL7) are up-regulated for a prolonged period (Figs. 3 and 4).
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Because exposure of mice to sham air or 0.8 ppm
O3 for 6 h up-regulated CXCL10 and CCL7 mRNA
levels, we sought to determine whether it also increased protein levels
of these chemokines. As shown in Fig. 5A, 0.8 ppm
O3 dramatically increased lung levels of both
CXCL10 and CCL7. Furthermore, 0.8 ppm O3 also
increased lung levels of CCR3, the receptor for CCL7 (Fig. 5B).
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We sought to determine the cell source of CCL7. As shown in Fig. 6, exposure of mice to air failed to
induce production of CCL7. Exposure of mice to 0.8 ppm
O3 increased epithelial levels of CCL7 (Fig. 6).
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To evaluate the role of the six chemokines up-regulated by
O3 in mediating airway inflammation induced by
O3, seven groups of mice were treated i.n. with
normal rabbit IgG (isotype control) or polyclonal rabbit anti-mouse
IgG against one of six murine chemokines, namely, CXCL1,2,3 (KC and
MIP-2), CXCL10, CCL3, CCL7, and CCL11 (Fig. 7). Exposure of control IgG-treated mice
to 0.8 ppm O3 for 6 h induced a vigorous
inflammatory response by 18 h postexposure. As expected, the Ab to
KC decreased the number of total cells by 64%
(p 0.01) and neutrophils by 73%
(p < 0.01). Surprisingly, the Ab to CXCL10
also decreased total cells by 58% (p < 0.05)
and neutrophils by 72% (p 0.01), whereas
the Ab to CCL7 decreased neutrophils by 63% (p
0.05). Abs to MIP-2, CCL3, and CCL11 did not inhibit recruitment of
either neutrophils or total cells. Macrophagic inflammation was not
significantly attenuated by any of these Abs (data not shown).
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Because cross-reactivity of anti-murine CXCL10 and
anti-CCL7 with KC could explain our unexpected observations of the
effects of these Abs on neutrophil recruitment, we sought to examine
the specificity of these Abs. We performed denaturing gel
electrophoresis of recombinant chemokines followed by Western blotting
using rabbit anti-murine chemokine Abs. As shown in Fig. 8, anti CXCL10 recognized CXCL10 but not
KC, CCL7, and CCL5. Likewise, the Abs to CCL7 and KC specifically
recognized CCL7 and KC, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Few investigators have evaluated the in vivo role of chemokines in mediating O3-induced airway inflammation. Koto et al. (12) reported that in vivo treatment with an Ab to the Gro family (anti-cytokine-induced neutrophil chemoattractant analogous to MIP-2) inhibited neutrophilic inflammation but not other cell types in rats. Consistent with the observations of Koto et al., we found that an Ab to the Gro family (KC) inhibited neutrophil recruitment. Unexpectedly, we also found that Abs to CCL7 and CXCL10 significantly inhibited O3-induced neutrophilic inflammation. The role of CXCL10 in neutrophil recruitment has not been described previously, but CXCL10 can be produced by neutrophils, and therefore can influence chemotaxis of CXCR3-expressing cells such as Th1 cells, which in turn may influence and regulate neutrophilic inflammation (32).
In the present study Abs directed against multiple chemokines, namely, CXCL10, CCL7, and KC, significantly inhibited ozone-induced neutrophil accumulation in the lung. An understanding of the specific roles of chemokines in orchestrating airway inflammation has been complicated by a number of different factors (33). First, simultaneous expression of multiple chemokines with partially overlapping functions is often observed. Second, chemokines often bind more than one chemokine receptor, and chemokine receptors typically bind more than one class of chemokine. Third, a likely scenario is that coordinated chemokine actions may have contributed to the reduced neutrophilic lung inflammation, as suggested by a study examining the roles of chemokines in allergic asthma. In that study, neutralization of several chemokines including CCL2, CCL3, CCL11, CCL12, and CCL22 was effective in inhibiting cellular recruitment (34). In this study, the chemokines were found to act in a coordinated fashion in contributing to the complex pathophysiology of allergic inflammation. In the current study, anti-chemokine Abs were administered 1 h before ozone exposure, and lung neutrophil accumulation was assessed 18 h after ozone exposure. During this interval, different chemokines may have influenced distinct processes underlying ozone-induced neutrophil accumulation in a framework of a coordinated chemokine network. The protocol of administration of the Abs in this study does not allow assessment of variable chemokine temporal activity or spatial activity because the Abs were administered before ozone exposure and ultimately to many sites in the lung via the i.n. route.
Oxidative stress from O3 exposure has been reported to induce a kinetically differential chemokine expression. For example, Zhao et al. (21) reported that 2 ppm O3 induced CXCL1,2,3 (MIP-2) mRNA expression that peaked 4 h postexposure, whereas CCL2 mRNA levels peaked at 24 h postexposure. In the present study, the CXCL1,2,3 (KC and MIP-2), CXCL10, CCL3, CCL7, and CCL11 were up-regulated at 0 h postexposure, whereas only CCL3, CCL7, and CXCL10 were still up-regulated 18 h postexposure, indicating differences in the kinetics of different chemokine expression. Because our data indicate that KC, CXCL10, and CCL7 orchestrate O3-induced neutrophilic lung inflammation, the kinetics of chemokine expression suggest that KC may have initiated neutrophil recruitment and that this process is later sustained by CXCL10 and CCL7. In contrast to our study, Johnston et al. (23) reported that 2.5 ppm O3 increased mRNA expression of induced CXCL1,2,3 (MIP-2), CXCL10, CCL3, and CCL11 in C57BL/6 mice as early as 2 h and that the up-regulation persisted for 24 h. These differences between the findings of investigators may reflect differences in the mouse strain (C57BL/6 in other studies vs BALB/c in the present study) used in different studies and suggest that genetic differences that appear to reside as a quantitative trait locus on chromosome 17 may be a factor that determines the inflammatory response to O3 (35).
Several investigators have attempted to elucidate the mechanism of O3-induced macrophage recruitment to the lungs. Exposure of animals to O3 has been shown to increase monocyte chemotactic activity in bronchoalveolar fluid (21). This activity was inhibited by an Ab directed against CCL2 in a monocyte chemotaxis assay (21). The in vivo role of chemokines was assessed by Koto et al. (12), who reported that in vivo administration of an Ab to cytokine-induced neutrophil chemoattractant inhibited neutrophilic but not macrophagic inflammation. Our findings are similar to the observations of Koto et al., and the Abs to the three chemokines that decreased neutrophil recruitment failed to decrease macrophage recruitment. These findings cannot be explained by the intrapulmonary route of administration of Abs because we and others have previously shown that anti-chemokine Abs are very effective in preventing lung inflammation in vivo when they are administered via this route (24, 25). An alternative explanation is that the dosage of administered Abs did not influence O3-induced macrophagic inflammation to the same extent as it influenced neutrophilic inflammation, or that the chemokines tested in this study do not regulate macrophage recruitment. Future studies may require administration of larger doses of each Ab and a larger repertoire of Abs to various chemokines to address these questions.
Oxidative stress from O3 exposure has been shown to induce airway hyperesponsiveness in humans (36, 37). These authors have suggested that because of these effects, O3 exposure is likely to contribute to asthma morbidity. Oxidative injury from O3 exposure has also been shown to induce recruitment of neutrophils in humans (7). Because severe and sudden-onset asthma is associated with airway neutrophilia, O3 exposure is likely to contribute significantly to asthma morbidity and mortality in this subset of patients (13, 14, 15, 16, 17, 18). Based on the data presented in this study, it is tempting to speculate that CXCL10 and CCL7 contribute to airway neutrophilic inflammation and asthma exacerbation in these patients after exposure to high O3-polluted air.
The Office of Air Quality Planning and Standards has set the National Ambient Air Quality Standards "criteria pollutants," including O3. The 1-h standard is 0.12 ppm, whereas the 8-h standard is 0.08 ppm. These levels are considerably lower than the dose that induced airway inflammation in the present study (0.8 ppm) and in previous studies involving exposure of mice to O3 (9, 35). These differences may represent a greater response of humans to O3 than mice, rats, and guinea pigs, as suggested by the observation that humans demonstrate an increase in neutrophilic inflammation even when they are exposed to 0.2 ppm O3 (8). These findings suggest that caution should be exercised when extrapolating murine data to humans. Nonetheless, the results of the present study suggest that future studies in humans should be directed at evaluating the role of CCL7 and CXCL10 in O3 oxidative stress-induced lung inflammation.
In summary, our results indicate that high concentrations of O3 increase recruitment of neutrophils and macrophages into the lungs, associated with an increase in expression of CXCL1,2,3 (KC and MIP-2), CXCL10, CCL3, CCL7, and CCL11. Exposure to 0.8 ppm O3 also increased lung protein levels of CXCL10, CCL7, and CCR3. In addition to the expected inhibition of neutrophil recruitment by the Ab to KC, administration of neutralizing Abs to murine CCL7 and CXCL10 before O3 exposure inhibited O3-induced neutrophil recruitment. These findings indicate that CCL7 and CXCL10 orchestrate oxidative stress-induced neutrophilic lung inflammation. This is the first report demonstrating an in vivo role of these chemokines in neutrophilic inflammation. These observations may have relevance to induction of neutrophilia in severe asthma.
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Acknowledgments |
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Footnotes |
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2 L.M. and B.K.C. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Sanjiv Sur, National Institutes of Health Asthma and Allergic Diseases Research Center and Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Medical Branch, Galveston, TX 77555-0762. E-mail address: Sasur{at}utmb.edu
4 Abbreviations used in this paper: BAL, bronchoalveolar lavage; i.n., intranasal(ly); 2m, 2-microglobulin; IP, IFN--inducible protein; MCP, monocyte chemoattractant protein; KC, mouse growth-related oncogene-; MIP, macrophage-inflammatory protein.
Received for publication June 22, 2001. Accepted for publication October 31, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am. J. Respir. Crit. Care Med. 153:530.[Abstract]
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S. A. Shore, E. S. Williams, and M. Zhu No effect of metformin on the innate airway hyperresponsiveness and increased responses to ozone observed in obese mice J Appl Physiol, October 1, 2008; 105(4): 1127 - 1133. [Abstract] [Full Text] [PDF]
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R. A. Johnston, T. A. Theman, F. L. Lu, R. D. Terry, E. S. Williams, and S. A. Shore Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation J Appl Physiol, June 1, 2008; 104(6): 1727 - 1735. [Abstract] [Full Text] [PDF]
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R. P. Bowler, M. Nicks, K. Tran, G. Tanner, L.-Y. Chang, S. K. Young, and G. S. Worthen Extracellular Superoxide Dismutase Attenuates Lipopolysaccharide-Induced Neutrophilic Inflammation Am. J. Respir. Cell Mol. Biol., October 1, 2004; 31(4): 432 - 439. [Abstract] [Full Text] [PDF]
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S. A. Shore, Y. M. Rivera-Sanchez, I. N. Schwartzman, and R. A. Johnston Responses to ozone are increased in obese mice J Appl Physiol, September 1, 2003; 95(3): 938 - 945. [Abstract] [Full Text] [PDF]
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K. Boztug, M. J. Carson, N. Pham-Mitchell, V. C. Asensio, J. DeMartino, and I. L. Campbell Leukocyte Infiltration, But Not Neurodegeneration, in the CNS of Transgenic Mice with Astrocyte Production of the CXC Chemokine Ligand 10 J. Immunol., August 1, 2002; 169(3): 1505 - 1515. [Abstract] [Full Text] [PDF]
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