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Friendly FireMichael Glenwood

Friendly Fire (continued)

FIVE YEARS AGO, Mabe visited her doctor complaining of asthma-like symptoms. Disconcerting as that was, it didn’t affect her everyday life. An inhaler was prescribed, and for a while, she used it only occasionally. Then, two years ago, it was like a switch had flipped.

“I was always very active—some people might say hyper,” she says. “Then, all of a sudden, I didn’t have any energy.”

An avid walker, Mabe grew depressed when she couldn’t exercise with Buddy, her Yorkshire terrier, and Holly, her English bulldog. Already petite, she lost weight, falling to an alarming 86 pounds.

Quite a few members of Mabe’s extended family had breathing issues. Her parents, both lifelong smokers, needed course after course of antibiotics to fight recurring infections before they died, one year apart, from chronic obstructive pulmonary disorder (COPD). Given her heredity and behavior—despite attempts to quit, Mabe still smokes—she envisioned a bleak future. COPD is an umbrella term that includes chronic bronchitis, emphysema and chronic asthma or asthmatic bronchitis. Most people have a little of this, a little of that, according to Robert Wise, MD, a Johns Hopkins School of Medicine professor of Pulmonary and Critical Care Medicine who holds a joint appointment in EHS at the Bloomberg School. All suffer declining lung function that can contribute to coughing, panic and death. COPD has no cure. Although smoking is a major risk factor, only one in seven smokers ends up with the disease.

Why Mabe’s parents? Why her?

Eager for answers, Mabe signed up for a research study investigating the link between genetics and COPD. More recently, she participated in a clinical trial instigated by Shyam Biswal’s research involving a new therapeutic agent: sulforaphane, a compound from broccoli sprout extract that was discovered in 1992 by Paul Talalay, MD, a professor in Pharmacology and Molecular Sciences who has a joint appointment in International Health at the Bloomberg School.

If scientists can prove in this study and successive clinical trials that sulforaphane works in people—like they previously demonstrated it worked in mice and in human cells in a dish—they will have found a potent intervention for a largely ignored public health issue affecting millions of Americans. (COPD is the No. 3 cause of death nationwide.) In addition, billions of people worldwide also might stand to benefit, mostly women and children whose lungs are chronically compromised from indoor air pollution caused by cooking fires fueled by cow dung and brush.

“Our discovery is not restricted to lung diseases only. If this pans out, it could be a big thing for public health.”
—Shyam Biswal

Sulforaphane works differently than existing anti-inflammatory agents, Biswal explains. Rather than tamp down inflammation by interfering with its various pathways, it ramps up a host’s defense system that’s been compromised by chronic inflammation. It breathes new life into Nrf2, a vital molecular player that’s effectively strangled by the “bad” inflammation that underpins not only COPD but also nearly every chronic disease imaginable.

Already, Biswal’s group has published research demonstrating in the lungs of COPD patients that a defect in the host defense results from a decrease in Nrf2. Additionally, they have shown that sulforaphane boosts Nrf2 levels and this enhances host defense in the lungs by improving the ability of macrophages to kill bacteria and making them more responsive to anti-inflammatory drugs such as steroids.

The ongoing clinical trial in which Mabe participated is double-blind, meaning that nobody knows yet whether their purple pills are placebos or contain high or low doses of broccoli sprout extract. But Mabe has a sneaking suspicion that she ingested sulforaphane and that it helped her. During the month-long trial when she dutifully swallowed her pills daily, she felt different. “It seemed like my air passages opened up more,” she reports. “I didn’t have any flare-ups during that time, and it’s odd that I wasn’t on my nebulizer for a whole month.”

The multicenter trial, coordinated here at Johns Hopkins and taking place at Temple University and SUNY Buffalo, to date has enrolled about half of the 90 participants needed to test whether feeding sulforaphane to people alters Nrf2 activity as assessed by anti-oxidant enzymes in macrophages. Reducing inflammation is ancillary.

“If we can’t hit this target, then we’ll have to step back and say, well, this works great in mice and in the test tube, but not when people ingest sulforaphane,” says Wise, who’s heading up the broccoli sprout extract clinical trial.

This wouldn’t be the first inflammation-related wonder-compound to fall apart in a human trial. But Wise is confident in the predictive quality of Biswal’s previous research. In addition, others have shown Nrf2 was increased in the nasal tissue of people who eat broccoli sprouts.

“We think if you can show that in the nose, we can show it in the lung,” Wise says.

That this strategy potentially may benefit nonsmokers who have chronic inflammation in the lungs is notable in the context of public health. Not incidentally, the WHO lists indoor air pollution from primitive household cooking fires as the leading environmental cause of death in the world.

“There’s no question that women and children in South America, Africa and South Asia are exposed for many hours a day in cooking huts to amazingly high levels of particulates from burning biofuels like cow dung, and that this leads to a condition that is akin to COPD,” Wise says. “They develop chronic cough and mucus production. They have airflow obstruction and die early.”

How their lungs are similar to or different from those compromised by tobacco-related COPD is unknown, prompting Biswal to remain hot on the Nrf2 trail.

Currently, he’s implanting particulate collected from cooking huts in India into the lungs of mice and testing how manipulations of the Nrf2 pathway affect disease outcomes. Next, he’s working on developing a breathing chamber for mice that would be analogous to the interior of a cooking hut.

“Our understanding is very weak in this area,” Biswal says, “and half the world’s population is at risk.”

If sulforaphane does, in fact, tackle COPD by boosting the defense system and rendering the immune system once again competent, complete with robust macrophages, what’s to prevent it from doing the same for those suffering from a gamut of inflammation-related diseases, including cystic fibrosis, HIV, cancer, asthma, psoriasis, sepsis, schizophrenia, atherosclerosis …?

“Nothing,” says Biswal. “Our discovery is not restricted to lung diseases only. If this pans out, it could be a big thing for public health.”


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