Zinc reverses lung damage and greatly improves patient survival

[Nov 28, 2022: Laura Coverson, Cedars-Sinai Medical Center]

Researchers have discovered that zinc, a common mineral, may reverse lung damage and improve survival for patients. (CREDIT: Creative Commons)

Investigators from the Women’s Guild Lung Institute at Cedars-Sinai have discovered that zinc, a common mineral, may reverse lung damage and improve survival for patients with a deadly age-related condition known as idiopathic pulmonary fibrosis (IPF).

Their findings, published in The Journal of Clinical Investigation, have the potential to change the landscape of treatment for patients with this disease, which most often affects those over age 50.

"This study has the potential to be a game changer," said Paul Noble, MD, chair of the Department of Medicine, director of the Women’sGuild Lung Institute and co-senior author of the study. "We identified a root cause of IPF-related lung damage and a potential therapeutic target that might restore the lungs’ ability to heal themselves."

Idiopathic pulmonary fibrosis, or IPF, affects 100,000 people in the U.S. and has no known cause. The condition, which leads to scarring of the lungs, called fibrosis, and progressive breathing difficulty, has no cure, and most patients die or require a lung transplant within three to five years of diagnosis. The incidence of IPF rises dramatically with age and affects men more often than women.

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Through this research, Cedars-Sinai investigators found that stem cells lining the air sacs in the lungs of patients with IPF lose their ability to process zinc, which is known to have a role in the growth of cells and healing damaged tissue.

Lack of zinc impairs the ability of the cells-called type 2 alveolar epithelial cells (AEC2s)-to regenerate. Restoring this ability via the molecular pathway the investigators traced in their experiments could lead to therapies that reverse IPF-related lung damage. The research team also generated a model of IPF in laboratory mice that can be used to develop new therapies.

Investigators first analyzed AEC2s from healthy lungs and also the lungs of patients with IPF. They discovered the cells from IPF lungs were missing a protein called zinc transporter 8 (ZIP8), which draws zinc into the cell.

In experiments with organoids-miniaturized, simplified versions of organs grown in a dish from patients’ tissues-they also observed that cells lacking the ZIP8 protein were unable to regenerate and form colonies as healthy cells should.

"The organoids with AEC2 cells that had the ZIP8 transporter were able to draw zinc into the cells, and then were able to regenerate and form more colonies," said Carol Liang, MD, associate professor of Medicine and first author of the study. "The cells without ZIP8 didn’t have a way to draw zinc in, so they formed fewer colonies. This is how we determined that it is ZIP8 that allows the cells to use zinc."

The investigators also used medication and deletion of the ZIP8 gene in mouse AEC2s to mimic IPF in laboratory mice. When they fed these mice a diet that included zinc supplements, their fibrosis improved.

Graphical abstract on how zinc works in the lungs. In young and healthy AEC2s, sufficient ZIP8 ensures adequate levels of intracellular zinc, SIRT1 activity, and AEC2 renewal capacity. However, in old AEC2s and IPF AEC2s, severely downregulated ZIP8 results in intracellular zinc deficiency and defective SIRT1 activity, which impairs AEC2 renewal. In addition, enzymes regulating NAD+ synthesis were downregulated in IPF AEC2s, further exaggerating SIRT1 impairment. Therefore, the optimal combinations of zinc, NAD+, and SIRT1 activation may restore AEC2 integrity and mitigate fibrosis. MT, metallothionein. (CREDIT: The Journal of Clinical Investigation)

"There have been few detailed studies of how zinc works in the lungs," said Dianhua Jiang, MD, PhD, professor of Medicine at Cedars-Sinai and co-senior author of the study. "Ours is the first to identify the detailed function of zinc in lung biology, specifically in IPF. It was particularly exciting to discover that zinc regulates the production of two other key molecules that promote tissue regeneration, nicotinamide adenine dinucleotide (NAD+) and Sirtuin1. These molecules have been implicated in tissue regeneration and aging."

Additional research is needed to help determine why the loss of ZIP8 occurs in the lung cells, and whether zinc supplements, alone or in combination with NAD+ and Sirtuin1 activators to help activate lung repair response, will reverse lung damage in human patients with this condition, Liang said, adding that answers to these questions could help thousands of patients.

Role of zinc dysregulation in lung disease. (CREDIT: MDPI.com)

The goal is to develop a clinical trial to determine if targeting the ZIP8/NAD+/Sirtuin1 pathway can improve lung function in IPF.

"The cause of IPF is unknown, but aging is a significant factor," Liang said. "The general population is aging, and the incidence of the disease is increasing. We need to find a cure, because we have more patients every year."

What are the stages of lung cancer?

According to the Cleveland Clinic, cancer is usually staged based on the size of the initial tumor, how far or deep into the surrounding tissue it goes, and whether it’s spread to lymph nodes or other organs. Each type of cancer has its own guidelines for staging.

Lung cancer staging

Each stage has several combinations of size and spread that can fall into that category. For instance, the primary tumor in a Stage III cancer could be smaller than in a Stage II cancer, but other factors put it at a more advanced stage. The general staging for lung cancer is:

Stage 0 (in-situ): Cancer is in the top lining of the lung or bronchus. It hasn’t spread to other parts of the lung or outside of the lung.
Stage I: Cancer hasn’t spread outside the lung.
Stage II: Cancer is larger than Stage I, has spread to lymph nodes inside the lung, or there’s more than one tumor in the same lobe of the lung.
Stage III: Cancer is larger than Stage II, has spread to nearby lymph nodes or structures or there’s more than one tumor in a different lobe of the same lung.
Stage IV: Cancer has spread to the other lung, the fluid around the lung, the fluid around the heart or distant organs.

Limited vs. extensive stage

While providers now use stages I through IV for small cell lung cancer, you might also hear it described as limited or extensive stage. This is based on whether the area can be treated with a single radiation field.

Limited stage SCLC is confined to one lung and can sometimes be in the lymph nodes in the middle of the chest or above the collar bone on the same side.
Extensive stage SCLC is widespread throughout one lung or has spread to the other lung, lymph nodes on the opposite side of the lung, or to other parts of the body.

What are the symptoms of lung cancer?

According to the Cleveland Clinic, most lung cancer symptoms look similar to other, less serious illnesses. Many people don’t have symptoms until the disease is advanced, but some people have symptoms in the early stages. For those who do experience symptoms, it may only be one or a few of these:

A cough that doesn’t go away or gets worse over time.
Trouble breathing or shortness of breath (dyspnea).
Chest pain or discomfort.
Wheezing.
Coughing up blood (hemoptysis).
Hoarseness.
Loss of appetite.
Unexplained weight loss.
Unexplained fatigue (tiredness).
Shoulder pain.
Swelling in the face, neck, arms or upper chest (superior vena cava syndrome).
Small pupil and drooping eyelid in one eye with little or no sweating on that side of your face (Horner’s syndrome).

Risk factors for lung cancer

While there are many factors that can increase your risk of lung cancer, smoking any kind of tobacco products, including cigarettes, cigars or pipes is the biggest single risk factor. Experts estimate that 80% of lung cancer deaths are smoking-related.

Other risk factors include:

Being exposed to secondhand tobacco smoke.
Being exposed to harmful substances, like air pollution, radon, asbestos, uranium, diesel exhaust, silica, coal products and others.
Having previous radiation treatments to your chest (for instance, for breast cancer or lymphoma).
Having a family history of lung cancer.

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Note: Materials provided above by Cedars-Sinai Medical Center. Content may be edited for style and length.

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