Treating ‘bad cholesterol’ may offer way to target PF, study finds – Pulmonary Fibrosis News

Problems with the metabolism of low-density lipoprotein (LDL) – also called “bad cholesterol” – and its receptor contribute to changes in lung cells that ultimately lead to pulmonary fibrosis (PF), an analysis of fibrotic lung tissue and cells and animals suggest the models.

Notably, a combination of two treatments approved to lower LDL, including statins, restored its receptor function and attenuated fibrosis, demonstrating for the first time that “pulmonary fibrosis can be attenuated through a pharmacological intervention that targets LDL-LDLR [LDL receptor] metabolism,” the scientists wrote.

These results were in the study, “LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis,» published in the journal Clinical and translational medicine.

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In PF, the thin walls of the tiny air sacs in the lungs where gas exchange occurs, called alveoli, begin to scar and thicken, causing shortness of breath. Studies indicate that type II alveolar cells (ATII) lining the alveoli are an early factor in lung scarring or fibrosis.

The low-density lipoprotein receptor (LDLR) is a protein on the surface of ATII cells that helps internalize LDL particles – small packages of proteins that transport fats and fatty substances (lipids), such as cholesterol, throughout the body. In ATII cells, low-density lipoproteins provide components for the production of a protective lubricant that is secreted into the alveoli to facilitate gas exchange.

Emerging evidence suggests that a disruption of the relationship between LDL and its receptor on ATII cells may contribute to PF.

A research team led by researchers from Fudan University in China conducted a series of experiments focusing on the LDL receptor in cellular and mouse models of PF, and they examined samples of fibrotic lung tissue from patients with idiopathic pulmonary fibrosis (IPF).

Evaluations of patient tissues showed low levels of activity of the LDL receptor gene and its receptor protein compared to samples from healthy people (controls). The results were similar in lung tissue isolated from people with systemic sclerosisa fibrotic disease caused by an impaired immune response.

In the IPF samples, the LDL receptor was expressed or produced at significantly lower levels in type II alveolar cells as well as in fibroblast cells – a cell found in connective tissue that plays a central role in fibrosis. Blood tests also confirmed that, compared to controls, IPF patients had significantly higher LDL levels.

Similarly, mice with bleomycin-induced pulmonary fibrosis also exhibited elevated LDL levels and low LDL receptor expression in lung tissue, again particularly in ATIIs and fibroblasts. Similar results were observed in three other mouse models of pulmonary fibrosis, suggesting that “LDL-LDLR expression was consistently disrupted,” the researchers wrote.

Fibrosis induced in mice lacking the gene encoding the LDL receptor resulted in significantly increased areas of fibrotic tissue and greater expression of pro-fibrotic genes compared to PF-induced but still healthy mice. Notably, mice lacking the LDL receptor showed fibrosis as early as seven days, “suggesting that mice with [LDL receptor] deficiency are more likely to [bleomycin]-FP induced,” the team wrote.

Mice lacking the LDL receptor also had increased numbers of immune cells in their lungs and higher levels of pro-inflammatory signaling proteins. Furthermore, the number of ATII cells that underwent programmed cell death (apoptosis) was markedly increased in these receptor-deficient mice compared to healthy PF-induced mice.

In ATII cells and endothelial cells lining blood vessels isolated from PF-induced LDL receptor-deficient mice, there was an increase in a marker for activated fibroblast cells known to generate scar tissue components. This increase in fibroblast-like ATII and endothelial cells in these mice was associated with a decrease in the LDL receptor.

Atorvastatin (sold under the brand name Lipitor) is a commonly prescribed statin drug to lower cholesterol levels. It works by enhancing the expression of LDL receptors and lowering cholesterol, especially LDL. Alirocumab (sold under the brand name Praying) is a second-line, antibody-based treatment for hypercholesterolemia approved for use in adults with cardiovascular disease.

PF-induced mice treated with a combination of atorvastatin and alirocumab showed fewer fibrotic areas in lung tissue compared to mice treated with atorvastatin or alirocumab alone.

The combination treatment also reduced the number of immune cells in the lungs, normalized LDL levels, improved LDL receptor expression, suppressed apoptosis, reduced the number of ATII and fibroblast-like endothelial cells, and reduced the risk of death.

Patterns of gene activity in mice after treatment with atorvastatin and alirocumab were similar to those in healthy mice. Dual therapy restored genes with greater or lesser activity after PF induction to normal levels.

“This study revealed that abnormal LDL-LDLR metabolism stimulates apoptosis, increases fibroblast-like endothelial and ATII cells, and activates fibroblasts, ultimately leading to FP,” the scientists wrote.

“Furthermore, we have shown that atorvastatin and alirocumab restore LDLR expression and LDL levels, providing proof of concept that restoration of LDL-LDLR metabolism by pharmacological agents that target LDL and /or LDLRs is a promising therapeutic strategy for fibrotic disorders,” they said. wrote.

The researchers also noted that their findings are clinically relevant and that “clinicians should pay particular attention to LDL and LDLR levels in patients with PF or other lung abnormalities.”

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