Novel properties of statins: suppression of the systemic and bone marrow responses induced by exposure to ambient particulate matter (PM10) air pollution

Exposure to ambient particulate matter (PM10) elicits systemic inflammatory responses that include the stimulation of bone marrow and progression of atherosclerosis. The present study was designed to assess the effect of repeated exposure of PM10on the turnover and release of polymorphonuclear leukocytes (PMNs) from the bone marrow into the circulation and the effect of lovastatin on the PM10-induced bone marrow stimulation. Rabbits exposed to PM10three times a week for 3 wk, were given a bolus of 5′-bromo-2′-deoxyuridine to label dividing cells in the marrow to calculate the transit time of PMNs in the mitotic or postmitotic pool. PM10exposure accelerated the turnover of PMNs by shortening their transit time through the marrow (64.8 ± 1.9 h vs. 34.3 ± 7.4 h, P < 0.001, control vs. PM10). This was predominantly due to a rapid transit of PMNs through the postmitotic pool (47.9 ± 0.7 h vs. 21.3 ± 4.3 h, P < 0.001, control vs. PM10) but not through the mitotic pool. Lovastatin delayed the transit time of postmitotic PMNs (38.2 ± 0.5 h, P < 0.001 vs. PM10) and shifted the postmitotic PMN release peak from 30 h to 48 h. PM10exposure induced the prolonged retention of newly released PMNs in the lung, which was reduced by lovastatin ( P < 0.01). PM10exposure increased plasma interleukin-6 levels with significant reduction by lovastatin ( P < 0.01). We conclude that lovastatin downregulates the PM10-induced overactive bone marrow by attenuating PM10-induced systemic inflammatory responses.

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Exposure to ambient particles accelerates monocyte release from bone marrow in atherosclerotic rabbits

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00425.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. L79-L85 ◽

Cited By ~ 35

Author(s):

Yukinobu Goto ◽

James C. Hogg ◽

Chih-Horng Shih ◽

Hiroshi Ishii ◽

Renaud Vincent ◽

...

Keyword(s):

Bone Marrow ◽

Transit Time ◽

Alveolar Macrophages ◽

Ambient Particles ◽

Cell Counts ◽

Thymidine Analog ◽

Rapid Release ◽

Dividing Cells ◽

Progression Of Atherosclerosis ◽

Stimulation Of

Exposure to air pollution [particulate matter, particles <10 μm (PM10)] causes a systemic inflammatory response that includes stimulation of the bone marrow (BM) and progression of atherosclerosis. Monocytes are known to play a key role in atherogenesis by migration into subendothelial lesions where they appear as foam cells. The present study was designed to quantify the BM monocyte response in Watanabe heritable hyperlipidemic (WHHL) rabbits after PM10exposure. WHHL rabbits were given twice weekly intrapharyngeal instillations of 5 mg of PM10for 4 wk to a total of 40 mg and compared with control WHHL or New Zealand White (NZW) rabbits. The thymidine analog 5′-bromo-2′-deoxyuridine was used to label dividing cells in the BM and a monoclonal antibody to identify monocytes in peripheral blood. The transit time of monocytes through the BM was faster in WHHL than in NZW rabbits (30.4 ± 1.9 h vs. 35.2 ± 0.9 h, WHHL vs. NZW; P < 0.05). PM10instillation exposure increased circulating band cell counts, caused rapid release of monocytes from the BM, and further shortened their transit time through the BM to 23.2 ± 1.6 h ( P < 0.05). The percentage of alveolar macrophages containing particles in the lung correlated with the BM transit time of monocytes (r2= 0.45, P <0.05). We conclude that atherosclerosis increases the release of monocytes from the BM, and PM10exposure accelerates this process in relation to the amount of particles phagocytosed by alveolar macrophages.

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Correction to: Involvement of TLR2 and TLR4 and Th1/Th2 shift in inflammatory responses induced by fine ambient particulate matter in mice

Inhalation Toxicology ◽

10.3109/08958378.2013.766079 ◽

2013 ◽

Vol 25 (3) ◽

pp. 178-178

Keyword(s):

Particulate Matter ◽

Inflammatory Responses ◽

Ambient Particulate Matter

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Health Effects of Ambient Particulate Matter—Biological Mechanisms and Inflammatory Responses to In Vitro and In Vivo Particle Exposures

Inhalation Toxicology ◽

10.1080/08958370701866313 ◽

2008 ◽

Vol 20 (3) ◽

pp. 319-337 ◽

Cited By ~ 97

Author(s):

Konrad Ludwig Maier ◽

Francesca Alessandrini ◽

Ingrid Beck-Speier ◽

Thomas Philipp Josef Hofer ◽

Silvia Diabaté ◽

...

Keyword(s):

Particulate Matter ◽

Health Effects ◽

Inflammatory Responses ◽

Ambient Particulate Matter ◽

Biological Mechanisms

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Involvement of TLR2 and TLR4 and Th1/Th2 shift in inflammatory responses induced by fine ambient particulate matter in mice

Inhalation Toxicology ◽

10.3109/08958378.2012.731093 ◽

2012 ◽

Vol 24 (13) ◽

pp. 918-927 ◽

Cited By ~ 51

Author(s):

Can Zhao ◽

Jiping Liao ◽

Weili Chu ◽

Suxia Wang ◽

Tongsheng Yang ◽

...

Keyword(s):

Particulate Matter ◽

Inflammatory Responses ◽

Ambient Particulate Matter

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The Effects of Ambient Particulate Matter on Human Alveolar Macrophage Oxidative and Inflammatory Responses

Journal of Toxicology and Environmental Health Part A ◽

10.1080/15287390903248901 ◽

2009 ◽

Vol 73 (1) ◽

pp. 41-57 ◽

Cited By ~ 71

Author(s):

K. Sawyer ◽

S. Mundandhara ◽

A. J. Ghio ◽

M. C. Madden

Keyword(s):

Particulate Matter ◽

Alveolar Macrophage ◽

Inflammatory Responses ◽

Ambient Particulate Matter ◽

Human Alveolar Macrophage

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Contribution of Lung Macrophages to the Inflammatory Responses Induced by Exposure to Air Pollutants

Mediators of Inflammation ◽

10.1155/2013/619523 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 114

Author(s):

Kunihiko Hiraiwa ◽

Stephan F. van Eeden

Keyword(s):

Bone Marrow ◽

Particulate Matter ◽

Epithelial Cells ◽

Air Pollutants ◽

Inflammatory Responses ◽

Vascular System ◽

Large Population ◽

Lung Epithelial Cells ◽

Lung Macrophages ◽

Proinflammatory Mediators

Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants.

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Phagocytosis of particulate air pollutants by human alveolar macrophages stimulates the bone marrow

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.5.l924 ◽

2000 ◽

Vol 279 (5) ◽

pp. L924-L931 ◽

Cited By ~ 49

Author(s):

Hiroshi Mukae ◽

James C. Hogg ◽

Dean English ◽

Renaud Vincent ◽

Stephan F. Van Eeden

Keyword(s):

Bone Marrow ◽

Transit Time ◽

Alveolar Macrophages ◽

Epidemiologic Studies ◽

Dependent Manner ◽

Ambient Particulate Matter ◽

Cell Counts ◽

Human Alveolar Macrophages ◽

Factor Α ◽

Dose Dependent

Epidemiologic studies have shown an association between the level of ambient particulate matter < 10 μm (PM10) and cardiopulmonary mortality. We have shown that exposure of rabbits to PM10stimulates the bone marrow. In this study, we determined whether human alveolar macrophages (AMs) that phagocytose atmospheric PM10produce mediators capable of stimulating the bone marrow. AMs incubated with PM10for 24 h produced tumor necrosis factor-α in a dose-dependent manner (86.8 ± 53.29 pg/ml with medium alone; 1,087.2 ± 257.3 pg/ml with 0.1 mg/ml of PM10; P < 0.02). Instillation of the supernatants from AMs incubated with 0.1 mg/ml of PM10into the lungs of rabbits ( n = 6) increased circulating polymorphonuclear leukocyte (PMN) and band cell counts as well as shortened the PMN transit time through the bone marrow (87.9 ± 3.3 h) compared with unstimulated human AMs (104.9 ± 2.4 h; P < 0.01; n = 5 rabbits). The supernatants from rabbit AMs incubated with 0.1 mg/ml of PM10( n = 4 rabbits) caused a similar shortening in the PMN transit time through the bone marrow (91.5 ± 1.6 h) compared with human AMs. We conclude that mediators released from AMs after phagocytosis of PM10induce a systemic inflammatory response that includes stimulation of the bone marrow.

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SYSTEMIC INFLAMMATORY RESPONSE INDUCED BY PARTICULATE MATTER AIR POLLUTION: THE IMPORTANCE OF BONE-MARROW STIMULATION

Journal of Toxicology and Environmental Health Part A ◽

10.1080/00984100290071685 ◽

2002 ◽

Vol 65 (20) ◽

pp. 1597-1613 ◽

Cited By ~ 83

Author(s):

Stephan F. van Eeden ◽

James C. Hogg

Keyword(s):

Bone Marrow ◽

Air Pollution ◽

Particulate Matter ◽

Inflammatory Response ◽

Systemic Inflammatory Response ◽

Bone Marrow Stimulation ◽

Marrow Stimulation

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Release of Polymorphonuclear Leukocytes From the Bone Marrow by Interleukin-8

Blood ◽

10.1182/blood.v92.3.1062.415k05_1062_1069 ◽

1998 ◽

Vol 92 (3) ◽

pp. 1062-1069 ◽

Cited By ~ 3

Author(s):

Takeshi Terashima ◽

Dean English ◽

James C. Hogg ◽

Stephan F. vanEeden

Keyword(s):

Bone Marrow ◽

Transit Time ◽

Polymorphonuclear Leukocytes ◽

Interleukin 8 ◽

Thymidine Analogue ◽

American Society

Several studies have shown that interleukin-8 (IL-8) causes a rapid granulocytosis with the release of polymorphonuclear leukocytes (PMN) from the bone marrow (BM) partially responsible for the granulocytosis. This study was designed to quantitate the release of PMN from the BM by IL-8 and measure the transit time of PMN through the marrow after IL-8 administration. The thymidine analogue, 5'-bromo-2'-deoxyuridine (BrdU), was used to label dividing PMN in the marrow and follow their release into the circulation after intravenous IL-8. This allowed us to calculate the transit time of PMN through the mitotic and postmitotic pools of BM. BrdU was infused intravenously into rabbits 24 hours before IL-8 (2.5 μg/kg). IL-8 caused a rapid, transient granulocytopenia (5.9 ± 0.4 at baseline v 0.2 ± 0.06 × 10/9L at 5 minutes, P < .05) followed by granulocytosis (8.4 ± 0.1 at 30 minutes, P < .05) associated with an increased number (0.3 ± 0.1 at baseline v1.2 ± 0.6 × 109/L at 30 minutes, P < .05) and percentage of band cells (P < .05), as well as a rapid increase in the number of BrdU-labeled PMN (PMNBrdU) in the circulation (0.09 ± 0.05 at baseline to 1.5 ± 0.6 × 109/L at 60 minutes, P < .05). The transit time of PMN through both the mitotic and postmitotic pools of BM was not affected by IL-8. To determine the marrow compartment from which the PMN were mobilized by IL-8, we quantitated PMN movement from the hematopoietic and sinusoidal compartments into the circulation. The fraction of PMNBrdU in both compartments was higher than in the circulating blood (P < .05) and the fraction and number of PMNBrdU in the sinusoids decreased with IL-8 treatment (P < .05). We conclude that the pool of PMN residing in the BM venous sinusoids are rapidly released into the circulation after administration of IL-8. © 1998 by The American Society of Hematology.

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