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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: 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.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

MH-S alveolar macrophage cells were simultaneously stimulated with the small molecule statin derivative LFA 878 and LMW HA (250 μg/ml) and cytokine production was measured. A, The small molecule statin derivative LFA 878 demonstrated a dose response inhibitory effect on LMW HA induced MIP 1-α expression with statistically significant inhibition noted at 20 μM (p=0.02) and maximal inhibition achieved at an 80 μM dose without evidence of cell death by Trypen blue assay (p=0.004); B) Simultaneous administration of LFA 878 (80 μM) also inhibited LMW HA induced RANTES production, although it did not reach statistical significance (p=0.08); C, There was no inhibitory effect of LFA 878 on LMW HA induced TNF-α production; D, Simultaneous administration of CD11a blocking antibodies (10 μg/ml) near the N-terminus of the I-domain inhibited LMW HA induction of MIP 1-α (Y17, p=0.022), as did an antibody directed towards talin protein that anchors LFA-1 to the cytoskeleton (H300, p=0.021). Whereas administration of M17/4 antibody specific for the carboxy-terminus of the I-domain of CD11a failed to inhibit LMW HA induction of MIP 1-α (p=0.428).
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Figure 4: MH-S alveolar macrophage cells were simultaneously stimulated with the small molecule statin derivative LFA 878 and LMW HA (250 μg/ml) and cytokine production was measured. A, The small molecule statin derivative LFA 878 demonstrated a dose response inhibitory effect on LMW HA induced MIP 1-α expression with statistically significant inhibition noted at 20 μM (p=0.02) and maximal inhibition achieved at an 80 μM dose without evidence of cell death by Trypen blue assay (p=0.004); B) Simultaneous administration of LFA 878 (80 μM) also inhibited LMW HA induced RANTES production, although it did not reach statistical significance (p=0.08); C, There was no inhibitory effect of LFA 878 on LMW HA induced TNF-α production; D, Simultaneous administration of CD11a blocking antibodies (10 μg/ml) near the N-terminus of the I-domain inhibited LMW HA induction of MIP 1-α (Y17, p=0.022), as did an antibody directed towards talin protein that anchors LFA-1 to the cytoskeleton (H300, p=0.021). Whereas administration of M17/4 antibody specific for the carboxy-terminus of the I-domain of CD11a failed to inhibit LMW HA induction of MIP 1-α (p=0.428).

Mentions: We utilized a novel low molecular weight statin derivative, LFA 878 (Novartis, Basel-Switzerland), to more specifically evaluate the role of LFA-1 in LMW HA mediated inflammatory signaling. LFA 878 was engineered to bind specifically to the I-domain of the CD11a arm of LFA-1. It has no reported effects on HMG CoA reductase activity, and has no other known epitopes (30). Alveolar macrophages were treated with LFA 878 at increasing doses prior to stimulation with LMW HA (250 ug/ml). Protein supernatants were collected at 18 hours and analyzed by ELISA for cytokine protein expression. LFA 878 inhibits MIP 1-α and RANTES expression but not TNF-a in a dose dependent manner (Figure 4A-C). Statistically significant inhibition occurred at a 40 uM dose (p=0.046). Cell death assessed by Trypan Blue exclusion assay was less than 5% at each dose.


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)

MH-S alveolar macrophage cells were simultaneously stimulated with the small molecule statin derivative LFA 878 and LMW HA (250 μg/ml) and cytokine production was measured. A, The small molecule statin derivative LFA 878 demonstrated a dose response inhibitory effect on LMW HA induced MIP 1-α expression with statistically significant inhibition noted at 20 μM (p=0.02) and maximal inhibition achieved at an 80 μM dose without evidence of cell death by Trypen blue assay (p=0.004); B) Simultaneous administration of LFA 878 (80 μM) also inhibited LMW HA induced RANTES production, although it did not reach statistical significance (p=0.08); C, There was no inhibitory effect of LFA 878 on LMW HA induced TNF-α production; D, Simultaneous administration of CD11a blocking antibodies (10 μg/ml) near the N-terminus of the I-domain inhibited LMW HA induction of MIP 1-α (Y17, p=0.022), as did an antibody directed towards talin protein that anchors LFA-1 to the cytoskeleton (H300, p=0.021). Whereas administration of M17/4 antibody specific for the carboxy-terminus of the I-domain of CD11a failed to inhibit LMW HA induction of MIP 1-α (p=0.428).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 4: MH-S alveolar macrophage cells were simultaneously stimulated with the small molecule statin derivative LFA 878 and LMW HA (250 μg/ml) and cytokine production was measured. A, The small molecule statin derivative LFA 878 demonstrated a dose response inhibitory effect on LMW HA induced MIP 1-α expression with statistically significant inhibition noted at 20 μM (p=0.02) and maximal inhibition achieved at an 80 μM dose without evidence of cell death by Trypen blue assay (p=0.004); B) Simultaneous administration of LFA 878 (80 μM) also inhibited LMW HA induced RANTES production, although it did not reach statistical significance (p=0.08); C, There was no inhibitory effect of LFA 878 on LMW HA induced TNF-α production; D, Simultaneous administration of CD11a blocking antibodies (10 μg/ml) near the N-terminus of the I-domain inhibited LMW HA induction of MIP 1-α (Y17, p=0.022), as did an antibody directed towards talin protein that anchors LFA-1 to the cytoskeleton (H300, p=0.021). Whereas administration of M17/4 antibody specific for the carboxy-terminus of the I-domain of CD11a failed to inhibit LMW HA induction of MIP 1-α (p=0.428).
Mentions: We utilized a novel low molecular weight statin derivative, LFA 878 (Novartis, Basel-Switzerland), to more specifically evaluate the role of LFA-1 in LMW HA mediated inflammatory signaling. LFA 878 was engineered to bind specifically to the I-domain of the CD11a arm of LFA-1. It has no reported effects on HMG CoA reductase activity, and has no other known epitopes (30). Alveolar macrophages were treated with LFA 878 at increasing doses prior to stimulation with LMW HA (250 ug/ml). Protein supernatants were collected at 18 hours and analyzed by ELISA for cytokine protein expression. LFA 878 inhibits MIP 1-α and RANTES expression but not TNF-a in a dose dependent manner (Figure 4A-C). Statistically significant inhibition occurred at a 40 uM dose (p=0.046). Cell death assessed by Trypan Blue exclusion assay was less than 5% at each dose.

Bottom Line: 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.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