Blood Journal
Leading the way in experimental and clinical research in hematology

Linking air pollution exposure with thrombosis

  1. Gökhan M. Mutlu,
  2. Paul J. Bryce, and
  3. G. R. Scott Budinger
  1. Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL
  2. Division of Allergy-Immunology, Northwestern University, Chicago, IL
  3. Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL

To the editor:

We read with interest the review by Franchini and Mannucci examining the link between exposure to particulate matter air pollution (PM) and an increased tendency toward thrombosis.1 In their discussion of the potential mechanisms by which PM might induce thrombosis, the investigators highlight the excellent work by Nemmar and colleagues suggesting that PM enhances the release of histamine by mast cells and the resulting activation of platelets increases the tendency toward thrombosis in hamsters administered intratracheal suspensions of diesel exhaust particles.2

We were surprised that the authors did not discuss an additional mechanism. In mice, we reported that the intratracheal administration of fine urban particulates or the inhalation of concentrated ambient particulate matter air pollution from Chicago resulted in an increase in the plasma levels of thrombin-antithrombin (TAT) complexes and accelerated arterial thrombosis in the ferric chloride carotid injury model via a mechanism that required the release of IL-6 from alveolar macrophages.3,4 This mechanism is attractive as resident macrophages in the lung are likely the “first responders” to inhaled particles5 and the prothrombotic effects of IL-6 have been well-described in the hematology literature.6 The potential clinical importance of this mechanism is highlighted by the frequent observation in human populations exposed to particulate matter that IL-6 or its transcriptional target, C-reactive protein, are increased the day after the exposure.79

Like Nemmar and colleagues, we reported that the administration of particles resulted in an influx of macrophages and neutrophils into the lung.3 However, we found that, while the instillation of PM increased histamine levels in the bronchoalveolar lavage (BAL) fluid (Figure 1A), the PM-induced increase in bronchoalveolar lavage fluid IL-6 was not affected by combined pretreatment of mice with pharmacologic inhibitors of histamine type I (H1R) and type 2 (H2R) receptors (Figure 1B). Furthermore, the PM-induced increase in BAL fluid IL-6 and the subsequent increase in plasma TAT complexes were similar in mice doubly deficient in the H1 and H2 receptors and their littermate controls (Figure 1C-D). As Franchini and Mannucci point out, much more work is required before we understand the important link between particulate matter air pollution exposure and thrombosis.

Figure 1

The effect of loss of histamine signaling in particulate matter–induced thrombin generation. Fine urban particulate matter (National Institute of Standards and Technology Standard Reference Material, SRM 1649a 200 μg/mouse in 50 μL PBS) or vehicle was administered intratracheally to 20-25 g, 6-8 week old male C57BL/6 mice as previously described.4 (A) After 24 hours BAL fluid was obtained and histamine levels were measured using a commercially available assay (EIA Histamine IM2015, Beckman Coulter). (B) Mice were treated with famotidine (10 mg/kg) and desloratadine (10 mg/kg) in 150 μL of PBS 4 hours before treatment with PM followed by an additional dose of famotidine 8 hours later. Twenty-four hours after PM administration, BAL fluid was obtained and IL-6 levels were measured as previously described (ELISA).3 (C,D) H1R and H2R receptor double knockout mice (H1R −/−/H2R−/−) or littermate controls were treated with PM and 24 hours later IL-6 and TAT were measured in BAL fluid and citrated plasma as previously described.3 The protocol for the use of mice was approved by the Animal Care and Use Committee at Northwestern University. N = 4 or 5 animals for each group. *P < .05 compared with PBS control; and NS, not significant using ANOVA with Bonferroni posttest comparison.

Authorship

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: G. R. Scott Budinger, MD, Division of Pulmonary and Critical Care Medicine, Northwestern University, 240 E Huron, M300, Chicago, IL 60611; e-mail: s-buding{at}northwestern.edu.

References