Alcoholic
liver disease generally has been associated with long-term chronic exposure
to or abuse of alcohol. But new research suggests that a person's immune system
in the liver mounts a highly orchestrated response to exposure to alcohol
much earlier than previously thought.
The progression of alcohol-induced liver disease follows a characteristic pattern. Prolonged exposure to alcohol creates large fatty globules in the liver, injury to liver cells, and inflammation. In some cases, the final result can be formation of excess connective tissue and cirrhosis, which can lead to liver failure.
The body's immune system has been implicated in this progression, but previous studies of its role focused primarily on long-term exposure. Laura E. Nagy, PhD, Pathobiology and Cleveland Clinic's Department of Gastroenterology and Hepatology, in a mouse model how the innate immune system in the liver responds to early exposure to alcohol. Surprisingly, she found initial exposure to ethanol – the intoxicating agent in alcohol – rapidly activates an ancient part of the innate immune system called the complement pathway. Complement evolved to protect us from pathogenic bacteria and viruses.
The innate immune system is how your body reacts immediately to an injury, such as when you get multiple cuts and scrapes while gardening. Most of the time, the innate immune system prevents bacteria and viruses from invading the body and also helps the body to repair and restore any damaged tissues. However, problems arise with prolonged or unnecessary inflammation – called chronic inflammation – that damages rather than repairs tissue.
Dr. Nagy and her team found that rapid activation of the complement pathway by alcohol in turn orchestrates other aspects of the immune system. For example, Dr. Nagy found that complement activates Kupffer cells, a specialized immune cell that resides in the liver. Kupffer cells then increase the production of molecules called cytokines. Cytokines, such as tumor necrosis factor-alpha, are essential to signaling and communication among immune cells.
“Our research illustrates the specific, dynamic interactions between multiple components of the innate immune response at early times in the liver's response to ethanol,” Dr. Nagy said.
“This suggests that ethanol exposure rapidly activates multiple components of our innate immune system. The interaction among these players contributes greatly to alcohol-induced liver injury,” she said. “Piecing together how the various components of the liver's immune response react adds to our understanding of the highly orchestrated response of the liver to insult, such as injury that occurs because of alcohol.”
These findings have practical implications for the managements of alcohol-induced liver disease. For example, early detection of changes in complement activation could facilitate early diagnosis of liver injury. Drugs that target the complement pathway might also be useful in arresting the disease before it progresses or in treating liver injury after it develops.
Dr. Nagy's research team included Sanjoy Roychowdhury, PhD, Megan R. McMullen, and Michele T. Pritchard, PhD, of the Department of Pathobiology; Amy Hise, MD, Case Western Reserve University's Center for Global Health and Disease; Nico van Rooijen, MD, Department of Molecular Cell Biology, VU University Medical Center, Amsterdam, The Netherlands; M. Edward Medof, MD, PhD, Case Western Reserve University's Department of Pathology; and Abram Stavitsky, PhD, VMD, Case Western Reserve University's Department of Molecular Biology and Microbiology. The research appeared in Hepatology (www3.interscience.wiley.com/journal/108562644/issue). The project was supported by grants from the National Institute on Alcoholism and Alcohol Abuse of the National Institutes of Health.