Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure

Our plain-English summary of Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure, by J.H. Shannahan, O. Alzate, W.M. Winnik, et al (Toxicology and Applied Pharmacology, 2012).

The study

• Authors: J.H. Shannahan, O. Alzate, W.M. Winnik, D. Andrews, M.C. Schladweiler, A.J. Ghio, S.H. Gavett, U.P. Kodavanti
• Journal: Toxicology and Applied Pharmacology
• Published: 2012;260(2):105-14
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA.

Published by Elsevier Inc.

In plain English

This was an animal study. The authors re-analysed stored blood serum from four rat experiments to look for blood markers of exposure to Libby amphibole (LA), a fiber sample from near Libby, Montana. Male rats of four strains, some healthy and some with heart disease, had LA placed directly into the windpipe, once or repeatedly; controls received only the carrier liquid. One experiment also used diesel exhaust particles. The authors note this is not a natural exposure route. One day after a single LA dose, two 'acute phase' proteins, part of a general reaction to inflammation, rose in all three strains tested. Lipocalin-2 also rose in those three strains, but osteopontin rose only in Wistar Kyoto rats. Metabolic syndrome markers showed little LA effect. Mesothelin, a mesothelioma marker, did not change consistently: it fell one day after a single dose in two strains, but rose in Wistar Kyoto rats after four weekly doses and a month's recovery. Diesel particles caused many similar but smaller changes. The authors concluded that LA exposure is associated with an acute phase response. They noted that no rats developed lung cancer or mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: retrospective analysis of serum samples from four separate rat toxicology studies (Studies A to D) using intratracheal instillation, with antibody-based assays in all four studies and global serum proteomic profiling in one (Study D)
• Who was studied: Male rats aged 11 to 12 weeks at purchase from four strains. Healthy strains were Wistar Kyoto (WKY) and Fischer 344 (F344). Cardiovascular-disease-compromised strains were spontaneously hypertensive (SH) and obese SH heart failure (SHHF). Group sizes were n=12/group for WKY, n=6/group for SH and SHHF in Study A, n=8 to 12/group for F344 in Studies B and C, and n=5/group for WKY in Study D.
• Exposure: Respirable fraction of Libby amphibole collected from the Rainy Creek Complex near Libby, Montana in 2007, given by intratracheal instillation. Study A: single dose of 0.25 or 1.0 mg in saline. Study B: single dose of 1.0 or 5.0 mg in dispersion medium. Study C: cumulative 1.0 or 5.0 mg in dispersion medium, given every other week 7 times over 13 weeks. Study D: 0.25 or 0.5 mg in saline weekly for 4 weeks, compared with 0.5 mg diesel exhaust particles (DEP). Controls received saline (WKY, SH, SHHF) or dispersion medium containing glucose, rat albumin and dipalmitoylphosphatidylcholine (F344).
• Main results:
  • Study A, single LA exposure: serum alpha-2-macroglobulin increased at 1 day after exposure in WKY and SH rats, and to a lesser degree in SHHF rats. It had returned to baseline by 3 months.
  • Study A: alpha-1-acid glycoprotein increased in WKY, SH and SHHF rats 1 day after 1 mg of LA. By 3 months only SH rats still showed significant increases.
  • Study B, F344 rats: no changes in alpha-2-macroglobulin or alpha-1-acid glycoprotein at 3 months or 1 year after a single LA exposure.
  • Study C, F344 rats given a cumulative 5 mg of LA over 13 weeks: significant increases in both alpha-2-macroglobulin and alpha-1-acid glycoprotein at 1 day and at 2 weeks after the last exposure.
  • Lipocalin-2 increased 1 day after 1 mg of LA in WKY, SH and SHHF rats and returned to baseline by 3 months. In Study D it stayed raised through 1 month in WKY rats repeatedly given 0.5 mg of LA. It was undetectable in all F344 rats.
  • Osteopontin increased in WKY rats 1 day after LA exposure and returned to baseline by 3 months. There were no changes in SH or SHHF rats.
  • Mesothelin did not change consistently across experiments. In Study A it decreased in WKY and SH rats 1 day after a single LA exposure and returned to baseline by 3 months. In Studies B and C it was not significantly changed in F344 rats. In Study D it was increased in WKY rats exposed weekly for 4 weeks and then given one month of recovery.
  • Study D, separate experiment: serum mesothelin was increased in WKY rats after four weekly LA exposures followed by one month of recovery.
  • Metabolic syndrome markers: leptin was higher in obese SHHF rats than in WKY and SH rats but was unaffected by LA. Adiponectin decreased in SH rats 1 day after 1 mg of LA. Insulin was reduced in SHHF rats 1 day after LA.
  • Study D proteomics, 1 day after four weekly LA doses in WKY rats: acute phase proteins rose, including ceruloplasmin, serum amyloid p-component, alpha-2-hs-glycoprotein and serine protease inhibitor. Serotransferrin, serum albumin and fetuin fell.
  • Table 1: serine protease inhibitor showed a fold change of 2.47 versus saline controls after 0.5 mg LA and 1.90 after 0.5 mg DEP.
  • DEP-exposed WKY rats showed many similar serum protein changes to LA-exposed rats, but the changes were smaller and fewer were significant.
  • Acute phase protein levels in LA-exposed WKY rats returned to baseline by 1 month (data not shown).
  • No differences in oxidatively modified serum proteins were detected after LA or DEP exposure.
• The authors' conclusion: The authors concluded that, like other air pollutants, LA exposure is associated with induction of an acute phase response. They found no biomarkers unique to LA because LA and DEP changes followed largely similar trends. They suggested the increases could have implications for systemic and pulmonary disease in people exposed to LA.
• Limitations the authors state:
  • Intratracheal instillation is not a natural route of exposure to asbestos fibers.
  • Exposure paradigms and LA doses differed between the four studies.
  • No lung cancer or mesothelioma occurred, which limits linking biomarker changes to these diseases.
  • Mesothelin's role as an early biomarker could not be confirmed.
  • Spontaneous diseases that develop in older F344 rats make it hard to compare exposure-related biomarker changes at chronic time points.
  • Strain-related differences in biomarker effects must be considered when extrapolating the findings to humans.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Libby vermiculite mine, Montana

All asbestos mines

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Biomarker, Asbestos Exposure, Environmental Exposure, Libby amphiboles, Glycoprotein, Osteopontin, Mesothelin.

Related studies

• The role of iron in Libby amphibole-induced acute lung injury and inflammation — J.H. Shannahan, A.J. Ghio, et al. (2011)
• Early and delayed effects of naturally occurring asbestos on serum biomarkers of inflammation and metabolism — U.P. Kodavanti, D. Andrews, et al. (2014)
• Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole — J.H. Shannahan, M.C. Schladweiler, et al. (2012)
• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice — M. Christofidou-Solomidou, R.A. Pietrofesa, et al. (2019)
• Pulmonary inflammatory and fibrotic responses in Fischer 344 rats after intratracheal instillation exposure to Libby amphibole — D.J. Padilla-Carlin, M.C. Schladweiler, et al. (2011)

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