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Lovastatin Inhibits Low Molecular Weight Hyaluronan Induced Chemokine Expression via LFA-1 and Decreases Bleomycin-Induced Pulmonary Fibrosis.

Hamblin MJ, Eberlein M, Black K, Hallowell R, Collins S, Chan-Li Y, Horton MR - Int J Biomed Sci (2014)

Bottom Line: 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).Lovastatin immediately inhibited the LMW HA induced cytokine MIP 1-α (p=0.001) independent of HMG CoA reductase.Lovastatin and LFA 878 inhibit LMW HA inflammatory signaling independent of HMG-CoA decreasing the chemotactic cytokine MIP 1-α.

View Article: PubMed Central - PubMed

Affiliation: University of Kansas Hospital, USA;

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.

No MeSH data available.


Related in: MedlinePlus

A, MH-S Alveolar Macrophages were stimulated with vehicle or LMW HA (250 μg/ml) with cell supernatants collected at various time points to establish a time course for peak MIP 1-α protein expression induced by LMW HA. Peak production occurs between 18-21 hours; B, MH-S Cells were stimulated with vehicle or varying doses of LMW HA with cell supernatants collected at 18 hours to establish the optimal dose of LMW HA to induce protein expression. Doses of 500 ug/ml induced more than 5% cell death by Trypan Blue Exclusion Assay in some experiments, so a dose of 250 ug/ml was considered the optimal dose to induce inflammatory expression.
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Figure 1: A, MH-S Alveolar Macrophages were stimulated with vehicle or LMW HA (250 μg/ml) with cell supernatants collected at various time points to establish a time course for peak MIP 1-α protein expression induced by LMW HA. Peak production occurs between 18-21 hours; B, MH-S Cells were stimulated with vehicle or varying doses of LMW HA with cell supernatants collected at 18 hours to establish the optimal dose of LMW HA to induce protein expression. Doses of 500 ug/ml induced more than 5% cell death by Trypan Blue Exclusion Assay in some experiments, so a dose of 250 ug/ml was considered the optimal dose to induce inflammatory expression.

Mentions: MH-S Alveolar Macrophages were stimulated with vehicle or LMW HA (250 µg/ml) with cell supernatants collected every three hours to establish a time course for peak MIP 1-α protein expression induced by LMW HA. Peak production occurs between 18-21 hours, and the 18-hour mark served as a time point for collection of cell supernatants for protein analysis in all future experiments (Figure 1A). Next, MH-S Cells were stimulated with vehicle or varying doses of LMW HA with cell supernatants collected at 18 hours to establish the optimal dose of LMW HA to induce protein expression. Doses of 500 µg/ml induced more than 5% cell death by Trypan Blue Exclusion Assay in some experiments, so a dose of 250 µg/ml was considered the optimal dose to induce inflammatory expression (Figure 1B).


Lovastatin Inhibits Low Molecular Weight Hyaluronan Induced Chemokine Expression via LFA-1 and Decreases Bleomycin-Induced Pulmonary Fibrosis.

Hamblin MJ, Eberlein M, Black K, Hallowell R, Collins S, Chan-Li Y, Horton MR - Int J Biomed Sci (2014)

A, MH-S Alveolar Macrophages were stimulated with vehicle or LMW HA (250 μg/ml) with cell supernatants collected at various time points to establish a time course for peak MIP 1-α protein expression induced by LMW HA. Peak production occurs between 18-21 hours; B, MH-S Cells were stimulated with vehicle or varying doses of LMW HA with cell supernatants collected at 18 hours to establish the optimal dose of LMW HA to induce protein expression. Doses of 500 ug/ml induced more than 5% cell death by Trypan Blue Exclusion Assay in some experiments, so a dose of 250 ug/ml was considered the optimal dose to induce inflammatory expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199473&req=5

Figure 1: A, MH-S Alveolar Macrophages were stimulated with vehicle or LMW HA (250 μg/ml) with cell supernatants collected at various time points to establish a time course for peak MIP 1-α protein expression induced by LMW HA. Peak production occurs between 18-21 hours; B, MH-S Cells were stimulated with vehicle or varying doses of LMW HA with cell supernatants collected at 18 hours to establish the optimal dose of LMW HA to induce protein expression. Doses of 500 ug/ml induced more than 5% cell death by Trypan Blue Exclusion Assay in some experiments, so a dose of 250 ug/ml was considered the optimal dose to induce inflammatory expression.
Mentions: MH-S Alveolar Macrophages were stimulated with vehicle or LMW HA (250 µg/ml) with cell supernatants collected every three hours to establish a time course for peak MIP 1-α protein expression induced by LMW HA. Peak production occurs between 18-21 hours, and the 18-hour mark served as a time point for collection of cell supernatants for protein analysis in all future experiments (Figure 1A). Next, MH-S Cells were stimulated with vehicle or varying doses of LMW HA with cell supernatants collected at 18 hours to establish the optimal dose of LMW HA to induce protein expression. Doses of 500 µg/ml induced more than 5% cell death by Trypan Blue Exclusion Assay in some experiments, so a dose of 250 µg/ml was considered the optimal dose to induce inflammatory expression (Figure 1B).

Bottom Line: 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).Lovastatin immediately inhibited the LMW HA induced cytokine MIP 1-α (p=0.001) independent of HMG CoA reductase.Lovastatin and LFA 878 inhibit LMW HA inflammatory signaling independent of HMG-CoA decreasing the chemotactic cytokine MIP 1-α.

View Article: PubMed Central - PubMed

Affiliation: University of Kansas Hospital, USA;

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.

No MeSH data available.


Related in: MedlinePlus