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National Toxicology Program

National Toxicology Program

UPDATE NewsletterUPDATE NewsletterDecember 2015

NIEHS Science Days offers insights on inflammation

By Robin Arnette
Reprinted from Environmental Factor, December 2015

Inflammation is a protective response the body uses to fight off infection from foreign organisms and to respond to injury caused by the environment. However, when the process persists over a long period of time, illness usually follows.

Attendees at the 2015 NIEHS Science Days were treated to a mini-symposium that discussed connections between inflammation and disease, with insights suggesting that inflammation could be a major player in the origins of certain human diseases.

The role of cholesterol trafficking

The first speaker was Michael Fessler, M.D., deputy chief of the NIEHS Immunity, Inflammation, and Disease Laboratory and head of the Clinical Investigation of Host Defense Group. Fessler discussed how oxysterols, an oxidized form of cholesterol, play a role in clearing inflammation in the lungs. He made the case that oxysterols may be important in acute respiratory distress syndrome, a lung condition with a mortality rate of 25 to 40 percent. Patients with this condition require a ventilator to breathe.

Fessler said cells, including macrophages that destroy invading organisms, avoid cholesterol overload by relying on a transporter called ABCG1 to export cholesterol from the cell. The absence of functioning ABCG1 leads to the inability to remove cholesterol, driving macrophages into a hyperinflammatory state and toward cell death.

Research performed by Fessler’s group found that an oxysterol, called 25-hydroxycholesterol, activates a protein, named liver X receptor (LXR), that is involved in clearing lung inflammation and promoting cholesterol export from cells. "25-hydroxycholesterol seems to be required to activate anti-inflammatory properties of LXR in the lung," Fessler said.

Peripheral nerves in environmental sensing

Sven-Eric Jordt, Ph.D., is interested in how sensory neurons become sensitized during injury and chronic pain conditions, such as inflammation. Jordt is an associate professor in anesthesiology at Duke University School of Medicine and studies transient receptor potential (TRP) channels, a superfamily of proteins involved in the senses of sight, smell, taste, touch, and hearing.

TRPs exist in the trigeminal nerves of the head and connect to the eyes, nose, and mouth. When a person is exposed to an airborne irritant, such as smoke, these nerve endings become excited. TRPs also exist in the dorsal nerves connecting to the skin, where heat and chemical stimuli are sensed.

Jordt said that in cases of chemically-induced inflammation, TRPA1 and sensory nerves promote an inflammatory response. His work has demonstrated that the lungs make peptides that rely on sensory nerves to provide biochemical cues.

"Our hypothesis is that inflammation activates pulmonary neuroepithelial cells, so that they produce neural peptides. The sensory neurons become more sensitive to these peptides, inducing coughing and other symptoms during a pulmonary infection from a pathogen that produces the endotoxin lipopolysaccharide," Jordt said.

Fungi are everywhere

According to Dori Germolec, Ph.D., head of the Systems Toxicology Group in the Toxicology Branch of the National Toxicology Program, mold spores are ubiquitous and are not a concern in healthy individuals unless they reach extremely high levels.

Germolec studies the inflammatory responses that occur after long-term exposure to the mold Aspergillus fumigatus. Colleagues at the National Institute for Occupational Safety and Health in Morgantown, West Virginia built an enclosed exposure system that provides a real-life inhalation exposure scenario. The system, which can be precisely controlled, is used to evaluate potential health effects following mold exposure.

The researchers exposed mice to one of three conditions — an air control, viable spores from A. fumigatus, and heat-inactivated spores, which are considered nonviable. They found that nonviable spores generate some inflammatory responses in rodent lungs, but the viable spores produced a much more potent inflammatory response, which appears to be related to spore germination in the lungs. Germolec explained that the life stages of mold are dependent on temperature and humidity, and spore germination can occur when conditions are optimum for growth.

"Everything we’ve looked at indicates that germination is critical to the development of the allergic response in mice," Germolec said.

  • Michelle Block

    Block’s research group has shown that protein radicals, reactive oxygen species, and the process of aging each can reprogram mouse microglial cells to be hypersensitive to innocuous stimuli. She is still looking for several specific factors that initiate this reprogramming. (Photo courtesy of Steve McCaw)

  • Abcg1 gene transform into lipid-laden foam cells

    Fessler’s group demonstrated that alveolar macrophages in mice that lack the Abcg1 gene transform into lipid-laden foam cells. (Photo courtesy of Michael Fessler)

  • Exposure to chlorine gas stimulates TRPs in human trigeminal nerves

    Exposure to chlorine gas stimulates TRPs in human trigeminal nerves. As a result, the neurons become activated. In this image, shading from blue to pink corresponds to increasing amounts of calcium uptake, an indicator of cellular activity. (Photo courtesy of Bret Bessac)

  • A House with mold

    A house affected by Hurricane Katrina shows contamination with molds, such as Stachybotrys chartarum, also known as toxic black mold. Germolec and her colleagues are using their exposure system to test the effects of these spores on mice. (Photo courtesy of Dori Germolec)

  • a microglial cell is activated by proinflammatory

    When a microglial cell is activated by proinflammatory triggers, reactive oxygen species modify the DNA and proteins inside of the cell, forming highly reactive molecules known as radicals. Protein and DNA radicals are shown in red, whereas nitric oxide synthase, an enzyme that produces the signaling molecule nitric oxide, is shown in green. (Photo courtesy of Michelle Block)

Neuroinflammation and the aging brain

The NIEHS Science Days committee typically invites a former trainee back to the institute to give a talk, and this year’s speaker fit right in with the presentations on inflammation. Michelle Block, Ph.D., is an associate professor in the Department of Anatomy and Cell Biology at Indiana University School of Medicine. At NIEHS, she worked with ://www.niehs.nih.gov/research/atniehs/labs/ln/pi/neuropharm/index.cfm">Jau-Shyong (John) Hong, Ph.D., in the Neuropharmacology Group.

Block explained that microglia, the main immune cells in the brain, act as sentinels that detect and respond to pathogens or environmental toxicants once they reach the brain. However, sometimes microglial cells stop being a neuronal police force, and instead become a source of chronic inflammation and oxidative stress.

Block said the switch is an important one, because neuroinflammation is a common denominator in several central nervous system (CNS) disorders, such as autism, Parkinson’s and Alzheimer’s diseases, stroke, multiple sclerosis, and traumatic brain injury.

"My obsession with understanding how and why microglia damage brain neurons started when I was at NIEHS," Block said. "We call the process neurotoxic reactive microgliosis, and we believe it underlies the chronic nature of CNS diseases, particularly many of those associated with aging."

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