Lovastatin inhibits low molecular weight hyaluronan induced chemokine expression via LFA-1 and decreases bleomycin-induced pulmonary fibrosis

Mark J. Hamblin, Michael Eberlein, Katharine Black, Robert Hallowell, Samuel Lester Collins, Yee Chan-Li, Maureen Horton

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Lovastatin has a unique ability to bind Leukocyte Function Antigen-1 (LFA-1), an integrin necessary for the full expression of inflammatory cytokines induced by the low molecular weight form of the extracellular matrix glycosaminoglycan hyaluronan (LMW HA). We hypothesized that lovastatin could inhibit LMW HA inflammatory signals via interaction with LFA-1, and attenuate bleomycin induced pulmonary fibrosis.

METHODS: We evaluated the effects of lovastatin, pravastatin, LFA-1 blocking antibodies, and a novel LFA-1 inhibitor LFA 878 on LMW HA induced cytokine production in alveolar macrophages. We evaluated the effect of lovastatin in a bleomycin model of lung injury.

RESULTS: Lovastatin immediately inhibited the LMW HA induced cytokine MIP 1-α (p=0.001) independent of HMG CoA reductase. Pravastatin showed no inhibitory profile when administered simultaneously with LMW HA. LFA-1 blocking antibodies and the small molecule statin derivative LFA 878 showed an inhibitory profile similar to lovastatin. Lovastatin showed decreased fibrosis on histopathology and improved survival at day 14, with a decrease in fibrocytes noted at day 8.

CONCLUSION: Lovastatin and LFA 878 inhibit LMW HA inflammatory signaling independent of HMG-CoA decreasing the chemotactic cytokine MIP 1-α. Lovastatin treatment improves survival in bleomycin lung injury with decreased fibrocytes and fibrosis.

Original languageEnglish (US)
Pages (from-to)146-157
Number of pages12
JournalInternational Journal of Biomedical Science
Volume10
Issue number3
StatePublished - Sep 15 2014

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Lovastatin
Pulmonary Fibrosis
Bleomycin
Hyaluronic Acid
HLA Antigens
Chemokines
Molecular Weight
Molecular weight
Antigens
Pravastatin
Blocking Antibodies
Lung Injury
Cytokines
Fibrosis
Hydroxymethylglutaryl CoA Reductases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Alveolar Macrophages
Glycosaminoglycans
Integrins
Extracellular Matrix

Keywords

  • Bleomycin
  • Fibrocytes
  • Hyaluronan
  • LFA-1
  • Lovastatin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lovastatin inhibits low molecular weight hyaluronan induced chemokine expression via LFA-1 and decreases bleomycin-induced pulmonary fibrosis. / Hamblin, Mark J.; Eberlein, Michael; Black, Katharine; Hallowell, Robert; Collins, Samuel Lester; Chan-Li, Yee; Horton, Maureen.

In: International Journal of Biomedical Science, Vol. 10, No. 3, 15.09.2014, p. 146-157.

Research output: Contribution to journalArticle

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AU - Chan-Li, Yee

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N2 - BACKGROUND: Lovastatin has a unique ability to bind Leukocyte Function Antigen-1 (LFA-1), an integrin necessary for the full expression of inflammatory cytokines induced by the low molecular weight form of the extracellular matrix glycosaminoglycan hyaluronan (LMW HA). We hypothesized that lovastatin could inhibit LMW HA inflammatory signals via interaction with LFA-1, and attenuate bleomycin induced pulmonary fibrosis.METHODS: We evaluated the effects of lovastatin, pravastatin, LFA-1 blocking antibodies, and a novel LFA-1 inhibitor LFA 878 on LMW HA induced cytokine production in alveolar macrophages. We evaluated the effect of lovastatin in a bleomycin model of lung injury.RESULTS: Lovastatin immediately inhibited the LMW HA induced cytokine MIP 1-α (p=0.001) independent of HMG CoA reductase. Pravastatin showed no inhibitory profile when administered simultaneously with LMW HA. LFA-1 blocking antibodies and the small molecule statin derivative LFA 878 showed an inhibitory profile similar to lovastatin. Lovastatin showed decreased fibrosis on histopathology and improved survival at day 14, with a decrease in fibrocytes noted at day 8.CONCLUSION: Lovastatin and LFA 878 inhibit LMW HA inflammatory signaling independent of HMG-CoA decreasing the chemotactic cytokine MIP 1-α. Lovastatin treatment improves survival in bleomycin lung injury with decreased fibrocytes and fibrosis.

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