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Published ahead of print on July 15, 2004, doi:10.1164/rccm.200402-235OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 891-897, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200402-235OC

Particulate Matter Air Pollution Stimulates Monocyte Release from the Bone Marrow

Yukinobu Goto, Hiroshi Ishii, James C. Hogg, Chih-Horng Shih, Kazuhiro Yatera, Renaud Vincent and Stephan F. van Eeden

The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia; and Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada

Correspondence and requests for reprints should be addressed to Stephan F. van Eeden, M.D., Ph.D., The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z1Y6 Canada. E-mail: svaneeden{at}mrl.ubc.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Particulate air pollution (PM10) stimulates alveolar macrophages (AMs) to release immature granulocytes from the bone marrow (BM) into the circulation. This study was designed to determine the effect of PM10 (ambient EHC-93 or inert carbon [CC]) instillation exposure on the monocyte release from the BM and the role of AM in this response. Monocyte precursors were labeled in the BM of rabbits in vivo by an intravenous injection of 5'-bromo-2'-deoxyuridine, and the effects of PM10 were determined by instillation either particles or supernatants of AM exposed to particles into the lungs. Instillation of EHC-93 (500 µg/ml) or supernatants from AM incubated with EHC-93 (100 µg/ml) increased circulating band cell counts (p < 0.05) and shortened the transit time of monocytes through the BM (35.5 ± 2.2 to 25.0 ± 1.5 hours or 36.2 ± 2.6 to 25.7 ± 1.8 hours, p < 0.05) compared with the control subject. CC (1%) instillation also shortened the monocyte BM transit time to 28.4 ± 1.9 hours (p < 0.05), but supernatants of AM incubated with CC did not. We conclude that exposure to atmospheric PM10 stimulates the production of mediators by AM, and these cytokines accelerate the monocyte release from the BM.

Key Words: air pollution • alveolar macrophages • bone marrow • cytokines • leukocytes

Epidemiologic studies have shown an association between exposure to urban particulate air pollution (particulates < 10 µm [PM10]) and pulmonary morbidity and mortality (1–3). This increase in mortality with low-grade PM10 air pollution was present even when adjusted for the other major risk factors such as cigarette smoking (2). Respiratory morbidity and mortality in both adults and children are related to admissions for pneumonia, asthma, pulmonary emboli, and chronic obstructive pulmonary disease (4, 5). This indicates that PM10 exposure may have a causal role in both acute and chronic respiratory conditions. The mechanisms for this adverse effect of inhaled particles on respiratory diseases are poorly understood.

We have shown that acute exposure to air pollution causes a systemic inflammatory response that induces a leukocytosis in both animals (6) and humans (7). This systemic response also causes bone marrow (BM) stimulation to release immature granulocytes into the circulation (6, 7). Functional studies (8–10) showed that these immature granulocytes are less deformable and less chemotactic, preferentially sequestrate in the lung microvessels, and migrate less efficiently into inflammatory sites compared with more mature cells, indicating their greater potential to damage tissue. We also recently showed that deposition of carbon particles in the lung stimulates the release of monocyte from the BM (11). This is of particular importance because the inflammatory cells that accumulate in the alveoli after repeated PM10 exposure are predominantly mononuclear (12). Collectively, these studies suggest that the BM response is critically important in the pathogenesis of adverse respiratory effects elicited by exposure to atmospheric particles.

Alveolar macrophages (AMs) and bronchial epithelial cells play an important role in processing inhaled airborne particles. Work from several laboratories, including our own, has shown that a large number of mediators are produced by AMs after phagocytosis of particles (13, 14), and several of these mediators stimulate the BM to release polymorphonuclear leukocytes (PMNs) (10, 15, 16). Several of these mediators also have the ability to increase the production and mobilization of monocytes from the BM (17, 18). Therefore, we postulate that phagocytosis of PM10 by AM induces the release of monocytes from the BM as a part of the systemic inflammatory response to particulate air pollution.

This study was designed to determine the role of mediators produced by AM when they phagocytose particles on monocyte production and release from the BM. AMs were exposed to both fine inert carbon (CC) or urban complex particles both in vivo and ex vivo to determine the importance of mediators release from AM on the BM monocyte response. We used the thymidine analogue 5'-bromo-2'-deoxyuridine (BrdU) to label the dividing monocyte precursors in the BM (11) and an ELISA to determine cytokine production by AM. Some of the results of these studies have been previously reported in an abstract form (19).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PM10 Particles
Ambient particles (EHC-93) were obtained from Environmental Health Directorate, Health Canada (Ottawa, ON, Canada) (20). Carbon particles (colloidal carbon [CC]; Fount India Drawing Ink, Pelikan, Hamburg, Germany) with an average size less than 1 µm were used (6) (see details in the online supplement).

Experimental Animals
Female New Zealand White rabbits (n = 33; 2.3 ± 0.6 kg) were used in this study. The studies were approved by the Animal Experimentation Committee of University of British Columbia.

Release of Monocytes from the BM after PM10 Exposure
Rabbits were anesthetized with 5% halothane, and 1 ml of normal saline (n = 6, control) or PM10 (500-µg EHC-93 mixed with 1 ml of saline, n = 6, or 1 ml of sterile saline containing 1% CC, n = 4) was instilled intrabronchially under fluoroscopy (6, 15). To label dividing cells in the BM, 100 mg/kg of BrdU (Sigma Chemical, St. Louis, MO) was infused intravenously 4 hours before the instillation (11). Blood samples were collected just before the instillation (baseline) and at intervals from 4 to 168 hours after BrdU injection. Differential white blood cell counts were determined by counting 200 leukocytes in randomly selected fields of view on Wright-stained blood smears. The rabbits were killed 7 days after the instillation, and the lungs were processed for histologic evaluation (see details in the online supplement) as previously described (6, 15).

Effect of Mediators from Human AM on the Monocyte Release from the Rabbit Marrow
AMs were recovered from bronchoalveolar lavage fluid obtained from surgically resected lungs of six patients (mean age, 60.9 years; range, 41–71 years; four males and two females) according to a previously described protocol (16). These AMs (1.0 x107 cells) were incubated for 24 hours with Roswell Park Memorial Institute (RPMI)-1640 medium alone (AM control; n = 5) or medium containing PM10 (100 µg/ml of EHC-93 [AM + EHC-93; n = 6] or 1% CC [AM + CC; n = 6]) as previous described (15, 16). These AM supernatants were instilled into the rabbit lung (0.6 ml/kg) after a protocol described previously here. Cytokine levels in these supernatants were measured by ELISA (21) (see details in the online supplement).

Immunohistochemical Detection of BrdU-labeled Monocytes
Cytospin preparations of leukocyte rich plasma were stained by a double-immunolabeling technique as previously described (11), using RbM2 (ICN Biomedicals, Aurora, OH), a monoclonal antibody specific for rabbit monocyte lysosomal antigen (22), and the anti-BrdU monoclonal antibody Bu20a (DAKO Laboratories, Copenhagen, Denmark) to determine the fraction of circulating BrdU-labeled monocytes (MOBrdU). All slides were coded and evaluated by investigators without knowledge of their origin, and their transit through the BM was calculated as described elsewhere (11).

Statistical Analysis
The results are expressed as means ± SEM and analyzed using a repeated-measure analysis of variance over time where the effect of multiple comparisons was corrected using the Bonferroni method. Differences between the EHC-93–exposed or CC-exposed groups and the control group were compared by using a paired or two-sample t test. A value of p less than 0.05 was considered as significant throughout the study.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Distribution of PM10 in the Lung
The AMs that contained particles in the PM10-exposed groups were distributed diffusely in rabbit lung. Higher percentages of particle-positive AMs were observed in the PM10 groups (16.8 ± 2.7%, CC; 19.8 ± 2.0%, EHC-93) compared with control group (1.0 ± 0.4%, PM10 versus control, p < 0.05) (Figure 1). There was no difference in the percentage of AM-containing particles between the CC-exposed and EHC-93–exposed groups.



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  		Figure 1. Distribution of particulates less than 10 µm (PM10) in alveolar macrophages (AMs). Both colloidal carbon (CC) and EHC-93 exposure resulted in a higher percentage of AMs with phagocytosed particles compared with normal saline exposure. There was no difference in the fraction of particle-positive AMs between the CC-exposed and EHC-93–exposed group. Each value represents the means ± SEM of four to six rabbits. *p < 0.05 versus the control group.

 
Effect of PM10 on the Release of Monocytes from the BM
Leukocytes in the circulation.
EHC-93 exposure increased white blood cell counts from 12 hours after the instillation, whereas the values in the CC exposed and control group remained unchanged (Figure 2A). Circulating monocyte counts in all groups did not change throughout the study period (Figure 2B). Band cell counts significantly increased 10 hours after the instillation of EHC-93 compared with the control group (Figure 2C).




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  		Figure 2. The circulating white blood cell (A), monocyte (B), and band cells counts (C) in the circulation of rabbits exposed to CC (open circles), EHC-93 (closed circles), or saline (control, open squares). White blood cell counts were expressed as a ratio of baseline values (before the instillation). EHC-93 exposure causes an increase in white blood cell counts (12 hours after the exposure) and band cells counts (10 hours after the exposure). Values of white blood cell, monocyte, and band cell counts in the CC-exposed rabbits were not different from the control. Values at each time point represent the means ± SEM of four to six rabbits. *p < 0.05 versus the control group.

 
MOBrdU in the circulation.
Figure 3 shows the release of MOBrdU in the circulation from the marrow after pulse labeling with BrdU with or without PM10 exposure. The fraction of MOBrdU in the circulation increased similarly in the CC-exposed and EHC-93–exposed groups, which were more rapid than the control group (8–12 hours, p < 0.05), and reached a peak at 12 hours after the instillation (16 hours, control) (Figure 3A). The number of MOBrdU in the circulation followed the same pattern as the percentage (Figure 3B).



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  		Figure 3. The release of BrdU-labeled monocytes (MOBrdU) (percentage, A; absolute number, B) into the circulation after acute exposure to CC (open circles), EHC-93 (closed circles), or saline (control, open squares). The data show that MOBrdU increased more rapidly in the PM10 (CC or EHC-93)-exposed group (a peak at 12 hours) compared with the control group (a peak at 16 hours). Each value represents the means ± SEM of four to six rabbits. *p < 0.05 versus the control group.

 
The size of the BM monocyte pool was evaluated by calculating the cumulative number of MOBrdU in the circulation as previously described (23). PM10 (CC or EHC-93) exposure did not change the BM monocyte pool size compared with the control (data not shown).

Effect of PM10 on the Release of Cytokines from AM
Figure 4 shows the macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein-1ß, granulocyte M-CSF (GM-CSF), interleukin (IL)-6, tumor necrosis factor-{alpha} (TNF-{alpha}), IL-1ß, IL-8, and monocyte chemotactic protein (MCP)-1 protein levels in supernatants of AMs incubated with medium alone (control), with CC, or with EHC-93. The GM-CSF, IL-6, TNF-{alpha}, IL-1ß, IL-8, and MCP-1 production by AM stimulated with EHC-93 significantly increased compared with control subjects. Carbon particles induced only an increase in IL-6 and TNF-{alpha} production by AM with other cytokine levels not different from control subjects.



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  		Figure 4. Macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein-1ß (MIP-1ß), granulocyte M-CSF (GM-CSF), interleukin (IL)-6, tumor necrosis factor-{alpha} (TNF-{alpha}), IL-1ß, IL-8, and monocyte chemotactic protein-1 (MCP-1) levels in supernatants of AMs incubated for 24 hours with medium alone (control; white bars), with CC (gray bars), or EHC-93 (black bars). GM-CSF, IL-6, TNF-{alpha}, IL-1ß, IL-8, and MCP-1 production by AM stimulated by EHC-93 increased significantly compared with control subjects. IL-6 and TNF-{alpha} production by AM stimulated by CC were also increased. Values represent the means ± SEM of six experiments. *p < 0.05 versus the control.

 
Supernatant Instillation
Instillation of the supernatant from AM incubated with EHC-93 into the lung (AM + EHC-93 group) caused an increase in circulating white blood cell (WBC) (Figure 5A) and band cell counts (10–24 hours, p < 0.05; Figure 5C) that were not seen in either the AM + CC group or AM group (control, AM incubated with medium alone). Circulating monocyte counts were unchanged in all groups (Figure 5B). The AM + EHC-93 group showed a rapid increase in the fraction (Figure 6A) and number (Figure 6B) of MOBrdU after 4 hours to reach a peak at 12 hours with a rapid disappearance from the circulation compared with those in control (24 and 36 hours, p < 0.05). The MOBrdU in the AM + CC group showed a similar pattern as the control with a same peak at 16 hours. The BM monocyte pool size was similar in all groups (data not shown).




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  		Figure 5. The circulating white blood cell (WBC) (A), monocyte (B), and band cells counts (C) in the circulation after instillation of supernatants from AM incubated with CC (AM + CC, open circles), EHC-93 (AM + EHC-93, closed circles), or medium alone (control, open squares). WBC counts were expressed as a ratio of baseline values (before the instillation). AM + EHC-93 group showed an increase of WBC counts and increased band cell counts (at 8–24 hours) after the supernatant instillation. Values at each time point represent the means ± SEM of five to six rabbits. *p < 0.05 versus the control group.

 


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  		Figure 6. The release of MOBrdU (percentage, A; absolute number, B) into the circulation after instillation of supernatants from AM incubated with CC (AM + CC, open circles), EHC-93 (AM + EHC-93, closed circles), or medium alone (control, open squares). The AM + EHC-93 group demonstrated a rapid increase in MOBrdU in the circulation to reach a peak at 12 hours followed by a rapid disappearance from the circulation compared with the control. The AM + CC group was not different from the control group. Each value represents the means ± SEM of five to six rabbits. *p < 0.05 versus the control group.

 
Transit Time of Monocytes through the Marrow
Table 1 shows the calculated mean transit time of MOBrdU through the BM after the instillation of PM10 or the supernatants into the lung. The results show that exposure to EHC-93 (p < 0.01) as well as CC (p < 0.05) shortened the transit time of MOBrdU through the marrow compared with the control subject. The instillation of supernatants from AM incubated with EHC-93 also resulted in a reduction in the transit time of MOBrdU through the marrow (p < 0.02), whereas the supernatants of the AM + CC group have a nonsignificant effect on transit time of monocytes through the marrow.


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  		TABLE 1. Transit times of monocytes through the bone marrow

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have recently developed a method to quantify the monocyte response in the BM of rabbits using the thymidine analogue BrdU to label dividing monocytes in the marrow (11). This method allows us not only to measure the transit time of monocytes through the marrow but also to study their behavior in the circulation and their recruitment into lung tissue (24). Using this technique, we have shown that the deposition of inert carbon particles into the lung stimulates a monocytic response from the marrow (11). In this study, we explore the effect of ambient particles (EHC-93, collected over a major North American city) on the marrow release of monocytes and determine the role of mediators release from AMs on this response. Our results show that AMs incubated with EHC-93 ex vivo produce mediators that stimulate the release of monocytes from the marrow similar to instillation exposure of the ambient particles themselves into the lung. They also demonstrate that supernatants of AM incubated with inert carbon particles and instilled into the lung did not shorten the transit time of monocytes through the BM in contrast to instilling the carbon directly into the lung. This could be due to the difference in the type and magnitude of mediators release from AMs incubated with ambient EHC-93 compared with inert carbon particles (Figure 4). We suspect that these monocytes released from the marrow by exposure to particulate matter air pollution contribute to the pathogenesis of the adverse effects of air pollution on both the heart and lung (25).

Several reports, including our own (12, 26, 27), have used instillation of particles and have documented similar cardiopulmonary change compared with controlled inhalation of ambient particles by animals. Instillation of particles allows more accurate control of the amount of particles that reaches the lower airways and lung cells that process these particles. especially in animals that are obligatory nose breathers. Controlled instillation of particles therefore provides a convenient experimental tool to quantify the local and the systemic inflammatory response elicited by exposure to particles. Previous studies from our laboratory have shown that instillation of either small inert carbon particles (6) or ambient air particles (12) into the lungs of rabbits stimulate the BM to accelerate the release of PMNs. This study extends these observations by showing that a single instillation exposure to either particle also accelerates the release of monocytes from the BM. We have used a light microscopic method to identify and quantify particles in AM and used that as a surrogate marker of AM exposure in vivo (the resolution of the light microscopy is 0.2–5 µm). Interestingly, the percentage of AMs containing particles 7 days after the acute exposure was similar in the CC-exposed and EHC-93–exposed groups (Figure 1), but the ambient particles accelerated the monocyte transit time through the marrow to a greater degree (Table 1). Because the original instilled amount of particles (500 µg/ml) was estimated to be equal between groups (12), this suggests that the particle composition determines the magnitude of the systemic inflammatory response elicited by exposure to air pollution. Similarly, Saldiva and colleagues reported a dose-dependent relationship between many components of concentrated ambient air particles and local lung inflammation measured as leukocytes in bronchoalveolar fluid in rats (28). Together, these studies suggest that exposure to inert particles is sufficient to generate a systemic inflammatory response but that particle composition determines the magnitude of this response.

Instillation exposure to EHC-93 increases the number of band cells in the circulation signifying BM stimulation, which confirms previous findings from our laboratory (6, 12, 15). Our previous studies have also shown that EHC-93 accelerates the transit time of PMNs through the marrow and promotes the release of immature PMNs into the circulation (12, 15). In this study, we showed that EHC-93 increases the release of monocytes from the marrow (Figure 3) and accelerates the transit of monocytes through the marrow (Table 1) without increasing the circulating monocyte counts (Figure 2B). These results are similar to those obtained during a pneumonia where the release of monocytes was accelerated from the marrow, and these results show that these newly released monocytes preferentially sequester in lung capillaries and migrate into air spaces (24). We suspect that the lack of an increase in circulating monocytes after EHC-93 exposure is due to preferential sequestration and recruitment of monocytes into the lung to assist with the particle clearance.

Our laboratory has previously shown that supernatants of both rabbit and human AMs incubated with EHC-93 and instilled into the lungs of rabbits have a similar effect on the marrow response. This model is a useful experimental tool to identify the AM-derived mediators responsible for the systemic response (BM stimulation) of particulate matter air pollution (15). We have used the same concentration of particles (100 µg/ml) as previously report, and the results show that supernatants of AM exposed ex vivo to EHC-93 also accelerate the transit time of monocytes through the BM (Table 1). This response was similar when a comparable dose of particles was instilled directly into the lung (previous studies have shown that an estimated 20% of particles instilled into the lung reached the alveoli) (12). These results suggest that mediators released by AM during phagocytosis are responsible for the stimulation of the BM to release monocytes either directly or indirectly. Our data also shows that GM-CSF, IL-6, IL-1ß, TNF-{alpha}, IL-8, and MCP-1 production by AMs were stimulated by EHC-93 (Figure 4). Several of these cytokines are involved in monocyte production and recruitment. The hematopoietic growth factors, GM-CSF and M-CSF, IL-6, and the ß-chemokines are thought to be important mediators for the production and mobilization of monocytes from the BM (17, 18). IL-6 is considered an important multifunctional cytokine involved in the regulation of a variety of cellular responses, including the induction of acute-phase protein synthesis, lymphocyte activation, and hematopoiesis. It is also a permissive factor for monocytic colony formation by human hematopoietic progenitor cells in combination with GM-CSF (29). Both IL-1 and IL-8 are known to stimulate the BM to release leukocytes as potent activators and chemotactic factors (30–32). Therefore, cytokines such as IL-6, IL-8, and GM-CSF stimulate the marrow to produce and release monocytes, whereas IL-1 and TNF-{alpha} induced the production of monocytic chemoattractants such as MCP-1 (17, 18, 33). MCP-1 belongs to the supergene family of C-C chemokines and has specificity for the recruitment of mononuclear leukocytes (34). Rosseau and colleagues (35) have shown that the induction of MCP-1 in AM is a major contributor to the recruitment of peripheral blood monocytes into the alveolar compartment. We suspect that a combination of cytokines and the colony-stimulating factors released from lung cells such as AM is responsible for the production and the marrow release of monocytes following exposure of atmospheric particles.

Instillation of CC particles into the lungs of rabbits accelerated the release of monocytes from the BM, but instillation of the supernatants of AM incubated with the CC did not (Table 1). This result contrasted with our previous report showing that both instillation of either CC or supernatant from AM incubated with CC initiated the release of PMN from the marrow using the same concentration of CC as in this study (6). These data indicate that supernatants generated by AM exposed to CC stimulate PMN but not monocyte release from the marrow, and we suspect that IL-6 and TNF-{alpha} (Figure 4) are essential mediators for PMN release from the BM but do not influence monoycte release from the marrow. Alternatively, carbon particles deposited directly into the lung could in addition to AM stimulate bronchial epithelial cells to release mediators that stimulate the BM monocyte response. Previous studies from our laboratory have shown that exposure of primary human bronchial epithelial cells to CC increases IL-1ß, IL-8, and leukemia inhibitory factor (LIF) production (21). Moreover, interaction between AMs and human bronchial epithelial cells after exposure to atmospheric particles causes a synergistic increase in GM-CSF and IL-6 production by AM (16). These studies underline the importance of phagocytosis of particles by several types of lung cells and interaction between these cells in stimulating the marrow to produce and release monocytes.

In summary, our results show that the deposition of particulate matter air pollution into the lung stimulates the BM to accelerate the transit time of monocytes through the marrow and promote their release into the circulation. AMs play a crucial role in this response by producing the mediators that cause BM stimulation. The results also show that phagocytosis of particles by lung cells contribute to this monocyte response and that the composition of the particles contributes to the magnitude of the systemic inflammatory response. These data suggest that mediators responsible for the monocyte release from the marrow are different from those for the marrow release of PMN. Monocytes are critically important to control and terminate the inflammatory response in the lung (24, 35) and are an integral effector cell in the pathogenesis of atherosclerosis (36). We suspect that an elevated production and release of monocytes from the marrow after exposure to atmospheric particles play an important role in the pathogenesis of both the local and systemic response to air pollution.


   Acknowledgments
 
The authors gratefully thank Diane Minshall and Caroline Hall for technical support and Health Canada for making the EHC-93 available.


   FOOTNOTES
 
Supported by a grant from the BC Lung Association, the Canadian Institutes of Health Research, and the Heart and Stroke Foundation; and a Career Investigators award from the American Lung Association and the William Thurlbeck Distinguished Researcher Award (S.F.V.E.).

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: Y.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.C.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C-H.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.F.V.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form February 24, 2004; accepted in final form July 14, 2004


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 DISCUSSION
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