Mitophagy in macrophages is a key step toward pulmonary fibrosis

February 24, 2016 by Jeff Hansen

Idiopathic pulmonary fibrosis is a devastating disease, and recently approved therapies have limited efficacy. Lungs become damaged with fibrotic scarring, and the median length of survival after diagnosis is three to five years.

The lung immune cells called are known to play a role in disease progression by starting an immune response and producing the reactive oxygen species that somehow lead to increased amounts of transforming growth factor beta, or TGF-β1. Macrophages are large white blood cells that are the initial defense-fighting cells in the lung.

In a paper published Feb. 23 in the journal Immunity, University of Alabama at Birmingham researchers show that the pathway leading to increased expression of TGF-β1—which provokes the destructive lung remodeling—involves Akt1 kinase-induction of and mitophagy. They also show that alveolar macrophages are the primary source of the damage-inducing TGF-β1 in the lung. Understanding such basic molecular mechanisms in the development and progression of pulmonary fibrosis may reveal ways to treat this disorder.

Mitophagy is a normal cell-protecting biological process in which mitochondria—the organelles that are the powerhouses of the cell —are selectively degraded if they are dysfunctional or damaged. Components from the degraded mitochondria are recycled to create new, functional mitochondria in the cell. Normally, mitophagy is a beneficial process. But the evidence from A. Brent Carter, M.D., professor in the Division of Pulmonary, Allergy and Critical Care Medicine, UAB Department of Medicine, and his colleagues shows that mitophagy plays a pathological role in alveolar macrophages to produce pulmonary fibrosis in a mouse model of pulmonary fibrosis.

"The biggest surprise," Carter said, "was something that intuitively makes no sense: We show that mitophagy is required for TGF-β1 production."

The UAB researchers found several lines of evidence for their conclusions, using either alveolar macrophages from a mouse model with bleomycin-induced lung injury, or human alveolar macrophages from patients with idiopathic pulmonary fibrosis.

First, conditional deletion of the TGF-β1 gene in mouse alveolar macrophages showed that TGF-β1 produced by the macrophages was required for pulmonary fibrosis in the . Second, mice with a conditional deletion of Akt1 in alveolar macrophages had impaired mitophagy and reduced production of TGF-β1.

Third, while Akt1 expression increases TGF-β1 expression, if the researchers inhibited mitophagy in vitro—using a mitochondria-targeted antioxidant or mRNA silencing of Parkin2, one of the proteins necessary for mitophagy—this abrogated TGF-β1 expression and fibroblast differentiation, despite elevated Akt1 expression. In vivo, mouse alveolar macrophages that had a conditional Park2 mutation, the gene for Parkin2, had abrogated production of TGF-β1 in bronchoalveolar lavage fluid.

Importantly, when the alveolar macrophages had a conditional Akt1 gene mutation or a conditional Park2 gene mutation, the mice showed increased alveolar macrophage apoptosis (the programmed cell death of old or damaged cells), and the mice were protected against pulmonary fibrosis.

Moreover, examination of human alveolar macrophages from patients showed increased pro-fibrotic gene expression and TGF-β1 gene expression in macrophages, compared with normal controls. These alveolar macrophages also showed increased mitophagy and apoptosis resistance, as compared with normal controls.

Altogether, these data suggest that Akt1-mediated mitophagy contributes to alveolar macrophage apoptosis resistance and pro-fibrotic polarization, and that autophagy in alveolar macrophages is required for development.

Pulmonary fibrosis

  • Means scarring in the lungs. Eventually, scar tissue makes it hard for oxygen to get into the blood.
  • Is a family of more than 200 different diseases that look very much alike, some with known causes. When the cause is not identified, it is called idiopathic PF.
  • The most common symptoms of PF are cough and shortness of breath.

Explore further: Researchers further illuminate pathway for treatment of cystic fibrosis

More information: Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis. DOI:

Related Stories

Researchers further illuminate pathway for treatment of cystic fibrosis

January 13, 2016
It is well established that people with cystic fibrosis (CF) have two faulty copies of the CFTR gene, but debate continues on the question of whether certain symptoms of the airway disease are caused by the mutation or if ...

Promising new target may treat pulmonary fibrosis

March 18, 2015
By uncovering the mechanism by which fibrous tissue cells in the lung multiply, researchers at The Saban Research Institute of Children's Hospital Los Angeles (CHLA), along with colleagues in Mexico and Canada, have identified ...

Researchers find potential treatment for fatal lung diseases

June 12, 2015
Researchers at the University of Georgia have discovered that the drug triciribine may reverse or halt the progression of pulmonary fibrosis and pulmonary hypertension, two respiratory diseases that are almost invariably ...

'Beneficial inflammation' may promote healing in pulmonary fibrosis

April 25, 2014
Inflammation has long been considered an integral part of the biological process that leads to deadly scarring in idiopathic pulmonary fibrosis. New research at National Jewish Health, however, suggests that a little inflammation ...

Recommended for you

Study explores whole-body immunity

November 21, 2017
Over the next few months, millions of people will receive vaccinations in the hope of staving off the flu—and the fever, pain, and congestion that come with it.

Drug could cut transplant rejection

November 21, 2017
A diabetes drug currently undergoing development could be repurposed to help end transplant rejection, without the side-effects of current immunosuppressive drugs, according to new research by Queen Mary University of London ...

Atopic eczema—one size does not fit all

November 21, 2017
Researchers from the UK and Netherlands have identified five distinct subgroups of eczema, a finding that helps explain how the condition can affect people at different stages of their lives.

Breast milk found to protect against food allergy

November 20, 2017
Eating allergenic foods during pregnancy can protect your child from food allergies, especially if you breastfeed, suggests new research from Boston Children's Hospital. The study, published online today in the Journal of ...

Zika-related nerve damage caused by immune response to the virus

November 20, 2017
The immune system's response to the Zika virus, rather than the virus itself, may be responsible for nerve-related complications of infection, according to a Yale study. This insight could lead to new ways of treating patients ...

How a poorly explored immune cell may impact cancer immunity and immunotherapy

November 17, 2017
The immune cells that are trained to fight off the body's invaders can become defective. It's what allows cancer to develop. So most research has targeted these co-called effector T-cells.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.