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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). Lovastatin inhibited (A) weight loss, and (B) mortality with an absolute mortality risk reduction of 45% at day 14 (n=20 in each group, χ2=10.6, p=0.014).
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Figure 5: 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). Lovastatin inhibited (A) weight loss, and (B) mortality with an absolute mortality risk reduction of 45% at day 14 (n=20 in each group, χ2=10.6, p=0.014).

Mentions: Bleomycin, a chemotherapeutic agent that has known pulmonary toxicity, is also known to increase total lung hyaluronan levels (35). Furthermore, transgenic animals that are unable to clear HA from the lungs due to lack of the HA receptor CD44 have increased damage and lung injury in response to bleomycin injury (12). We hypothesized that lovastatin, in part by inhibiting LMW HA induced inflammatory gene expression, would attenuate bleomycin-induced lung inflammation and fibrosis and improve overall mortality. WT mice were treated with lovastatin (20 mg/kg) or vehicle control (volume equivalent) by oral gavage beginning one day prior to intratracheal administration of bleomycin (0.025 U/20 g) and daily thereafter for 14 days. We monitored the mice for weight loss and survival. In the initial days following bleomycin administration weight loss was similar in both groups, but beginning on day 5 the lovastatin treated mice were noted to have less weight loss than our placebo group (Figure 5A). Animals treated with lovastatin had a clear survival advantage (ARR=45%) (Figure 5B). Thus, lovastatin attenuated mortality after bleomycin injury.


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). Lovastatin inhibited (A) weight loss, and (B) mortality with an absolute mortality risk reduction of 45% at day 14 (n=20 in each group, χ2=10.6, p=0.014).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: 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). Lovastatin inhibited (A) weight loss, and (B) mortality with an absolute mortality risk reduction of 45% at day 14 (n=20 in each group, χ2=10.6, p=0.014).
Mentions: Bleomycin, a chemotherapeutic agent that has known pulmonary toxicity, is also known to increase total lung hyaluronan levels (35). Furthermore, transgenic animals that are unable to clear HA from the lungs due to lack of the HA receptor CD44 have increased damage and lung injury in response to bleomycin injury (12). We hypothesized that lovastatin, in part by inhibiting LMW HA induced inflammatory gene expression, would attenuate bleomycin-induced lung inflammation and fibrosis and improve overall mortality. WT mice were treated with lovastatin (20 mg/kg) or vehicle control (volume equivalent) by oral gavage beginning one day prior to intratracheal administration of bleomycin (0.025 U/20 g) and daily thereafter for 14 days. We monitored the mice for weight loss and survival. In the initial days following bleomycin administration weight loss was similar in both groups, but beginning on day 5 the lovastatin treated mice were noted to have less weight loss than our placebo group (Figure 5A). Animals treated with lovastatin had a clear survival advantage (ARR=45%) (Figure 5B). Thus, lovastatin attenuated mortality after bleomycin injury.

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