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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

C57/BL6 mice were treated once daily with lovastatin 20 mg/kg by oral gavage one day prior to bleomycin lung injury (0.025 U/20g). A, Bronchoalveolar lavage at day 8, demonstrated significant differences between lovastatin and placebo treatment groups (n=3 in each group). Lovastatin treated mice had a markedly increased number of macrophages (p=0.002) and a statistically significant decrease in lymphocytes (p=0.01); B, The percentage of fibrocytes (CD45+/collagen+ cells) from whole lung lysates harvested at day 8 were also significantly decreased in lovastatin treated mice (p=0.001); C, Lovastatin treated mice demonstrated decreased histologic lung damage on hematoxylin and eosin stain with a decrease in collagen staining on Masson’s Trichrome Stain at day 14.
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Figure 6: C57/BL6 mice were treated once daily with lovastatin 20 mg/kg by oral gavage one day prior to bleomycin lung injury (0.025 U/20g). A, Bronchoalveolar lavage at day 8, demonstrated significant differences between lovastatin and placebo treatment groups (n=3 in each group). Lovastatin treated mice had a markedly increased number of macrophages (p=0.002) and a statistically significant decrease in lymphocytes (p=0.01); B, The percentage of fibrocytes (CD45+/collagen+ cells) from whole lung lysates harvested at day 8 were also significantly decreased in lovastatin treated mice (p=0.001); C, Lovastatin treated mice demonstrated decreased histologic lung damage on hematoxylin and eosin stain with a decrease in collagen staining on Masson’s Trichrome Stain at day 14.

Mentions: Lovastatin treatment also attenuated inflammation in bleomycin lung injury. Bronchoalveolar lavage (BAL) specimens on day 8 after bleomycin revealed statistically significant differences between absolute numbers of macrophages (p=0.002) and lymphocytes (p=0.01) between the treatment groups (Figure 6A). Lovastatin treated mice had increased numbers of macrophages but about half as many lymphocytes when compared to placebo.


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)

C57/BL6 mice were treated once daily with lovastatin 20 mg/kg by oral gavage one day prior to bleomycin lung injury (0.025 U/20g). A, Bronchoalveolar lavage at day 8, demonstrated significant differences between lovastatin and placebo treatment groups (n=3 in each group). Lovastatin treated mice had a markedly increased number of macrophages (p=0.002) and a statistically significant decrease in lymphocytes (p=0.01); B, The percentage of fibrocytes (CD45+/collagen+ cells) from whole lung lysates harvested at day 8 were also significantly decreased in lovastatin treated mice (p=0.001); C, Lovastatin treated mice demonstrated decreased histologic lung damage on hematoxylin and eosin stain with a decrease in collagen staining on Masson’s Trichrome Stain at day 14.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: C57/BL6 mice were treated once daily with lovastatin 20 mg/kg by oral gavage one day prior to bleomycin lung injury (0.025 U/20g). A, Bronchoalveolar lavage at day 8, demonstrated significant differences between lovastatin and placebo treatment groups (n=3 in each group). Lovastatin treated mice had a markedly increased number of macrophages (p=0.002) and a statistically significant decrease in lymphocytes (p=0.01); B, The percentage of fibrocytes (CD45+/collagen+ cells) from whole lung lysates harvested at day 8 were also significantly decreased in lovastatin treated mice (p=0.001); C, Lovastatin treated mice demonstrated decreased histologic lung damage on hematoxylin and eosin stain with a decrease in collagen staining on Masson’s Trichrome Stain at day 14.
Mentions: Lovastatin treatment also attenuated inflammation in bleomycin lung injury. Bronchoalveolar lavage (BAL) specimens on day 8 after bleomycin revealed statistically significant differences between absolute numbers of macrophages (p=0.002) and lymphocytes (p=0.01) between the treatment groups (Figure 6A). Lovastatin treated mice had increased numbers of macrophages but about half as many lymphocytes when compared to placebo.

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