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Effects of THS toxins on mechanical and drug-induced injury

Institution: University of California, Riverside
Investigator(s): Manuela Martins-Green, Ph.D.
Award Cycle: 2013 (Cycle 22) Grant #: 22RT-0141H Award: $450,896
Subject Area: Environmental Exposure/Toxicology
Award Type: Research Project Awards

Initial Award Abstract

Tobacco smoking is one of the leading avoidable causes of death. It leads to cancer, hardening of the arteries, and lung and kidney disease. Moreover, it also severely affects how people heal. Wounds (both internal and external) of smokers and of those exposed to smoking heal poorly. They can even remain as open sores that can be sites for local infection that can either lead to healing with excessive scar or can spread systemically in the body and cause death. In cases of extensive burns, for example, the scarring can cause disfiguring and may impair normal post-recovery movement. Scarring after injury is also highly relevant to internal organ injury because it replaces functioning tissue with scar tissue: Examples are heart attack, liver damage by alcohol or Tylenol, and obstruction of the bowel after surgery.

This proposal addresses a recently-discovered smoking threat called third-hand smoke (THS). THS is derived from the repeated deposition and aging of tobacco chemicals from Second Hand Smoke on surfaces in homes and cars. THS is a stealth toxin present in households of smokers; it exposes children and the elderly to harmful chemicals without their knowledge. Although we know that many of the chemicals in THS are toxic and have the potential to cause cancer, we know little about the effects of THS on health overall.

The overall goal of this study is to identify how THS exposure affects response to injury and healing, so as to inform policy makers of the dangers of this newly recognized threat. Without the underlying scientific knowledge, it is impossible to develop and enforce effective policies to minimize exposure. We have already shown (with support from an Exploratory/Developmental Research Award) that mice exposed to THS under conditions that mimic human exposure have abnormal healing of the skin and develop non-alcoholic fatty liver disease (NAFLD), a disease that impairs liver function; liver is critical for the metabolism of drugs such as Tylenol and hence exposure to THS and Tylenol could lead to severe damage to the liver.

In the studies proposed here, we will determine exactly how THS affects response to injury and healing of skin and liver. Injuries to these organs are common in children—in skin, from accidental cuts and abrasions; and in liver, from Tylenol used for pain and fever. Although typical doses of Tylenol cause only minor harm, serious injury is possible from chronic or repeated use, especially when exposure to smoke toxins occurs.

We propose that chemicals in THS change the wound environment in both skin and liver in ways that interfere with normal healing. To test this idea we will identify and analyze the changes that occur in THS-exposed mice, and determine exactly how these changes disrupt healing. We use well-established systems and methods to ensure success in identifying which molecules are involved in the THS effects.

These studies are important because they will determine the mechanisms by which THS induces abnormal healing, and how it does so. Where possible, we will also suggest appropriate ways to restore the normal healing process. Our results may also point toward prevention and treatments for similar injury of the heart, kidney and lung. And, they will provide regulatory agencies with the experimental evidence to formulate and enforce policies to reduce exposure of infants, children, adults, elderly and workers in indoor environments where smoking occurs