Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study

Abstract

The role of an atherogenic diet in causing pulmonary fibrosis has received little attention and simvastatin has been shown to reduce pulmonary fibrosis in animal models. To determine if an atherogenic diet can induce pulmonary fibrosis and whether simvastatin treatment is beneficial by up-regulating heat shock protein 70 and 90. New Zealand white rabbits (n = 15) were divided: Group 1 (control); Group 2 (MC) received a normal rabbit diet with 1% methionine plus 0.5% cholesterol (atherogenic diet). Group 3 received the same diet as the MC group plus 5 mg/kg/day simvastatin orally (MCS). After 4 weeks, the lungs were collected and analysed. Picrosirus red staining of lung interstitial collagen content showed that the atherogenic diet increased fibrosis 2.9-fold (P < 0.05), bronchiole adventitial collagen was increased 2.3-fold (P < 0.05) and bronchiole epithelium was increased 34-fold (P < 0.05), and simvastatin treatment severely reduced this effect (P < 0.05). Western blot analysis showed that the atherogenic diet significantly reduced lung Hsp70 protein by 22% (P < 0.05) and Hsp90 protein by 18% (P < 0.05) and simvastatin treatment did not affect this result. However, aortic hyper-responsiveness to vasoconstrictors (angiotensin II and phenylephrine) were markedly reduced by simvastatin treatment. We report that an atherogenic diet stimulates pulmonary fibrosis and reduces lung Hsp70/Hsp90 protein concentration. Simvastatin impairs this by mechanisms unrelated to Hsp70/Hsp90, but possibly a reduction in angiotensin II receptor or alpha adrenergic receptor pathways. These results could have implications in idiopathic pulmonary fibrosis.

LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis

“…An increasing body of evidence has indicated that statins may have a beneficial effect on clinical outcomes in PF and even in COVID‐19 23,36–38 . By searching all the literature investigating the association of statins with PF, including 7 clinical studies 23,24,39–43 and 18 experimental studies, 24,36,44–59 we found that almost all studies trends to indicate that the statins are protective for PF (Supporting information Table S3). It is believed that lipophilic statins are taken up faster by PF lung tissue through passive diffusion than through active uptake 60 .…”

Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

“…Altered lipid profiles have been reported IPF BAL fluid [ 186 ], IPF lung [ 187 ], and IPF type II AECs [ 188 ]. In line with these findings, the cholesterol-lowering agent simvastatin has been shown able to reduce atherogenic diet-elicited pulmonary fibrosis by downregulating Hsp70/Hsp90 protein concentration in the lung [ 189 ].…”

The Effect of Cardiovascular Medications on Disease-Related Outcomes in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis

“…In vitro study on lung fibroblasts showed that simvastatin can inhibit the induction of collagen production by TGF-β ( Oka et al, 2013 ). In vivo study showed that simvastatin treatment severely reduced fibrosis, bronchiole adventitial collagen, and bronchiole epithelium ( Kruzliak et al, 2015 ). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in the management of cardiovascular diseases and systemic hypertension ( Chobanian et al, 2003 ).…”