Blocking adhesion protein may reduce lung damage from radiation
Lung inflammation, lung damage, and diminished lung performance caused by radiation of the lungs are reduced in mice genetically engineered to lack a protein called intercellular adhesion molecule-1, or ICAM-1, researchers report in the May 15 issue of the Journal of the National Cancer Institute.
These findings suggest that drugs that block the activity of ICAM-1 could be used to prevent radiation therapy-related problems, conclude Dennis E. Hallahan, M.D., and his colleagues at Vanderbilt University in Nashville, Tenn.
Therapeutic chest irradiation often results in complications such as radiation pneumonitis (lung inflammation), pulmonary fibrosis (the accumulation of collagen, or scar tissue, in the lungs), and respiratory insufficiency (diminished lung performance). These problems limit the ability of physicians to effectively treat lung cancer using radiation.
Earlier studies suggested that acute inflammation could be prevented in radiation-treated mice that were genetically engineered to lack ICAM-1, a cell adhesion molecule that mediates the recruitment of leukocytes, or white blood cells, to the lungs. Leukocytes contribute to inflammation, which leads to fibrosis and decreased lung performance. However, it remains unclear whether blocking ICAM-1 expression can also prevent fibrosis and respiratory insufficiency.
To determine the role of ICAM-1 in pulmonary fibrosis and lung performance, Hallahan and his coworkers treated groups of 10 mice with either mock irradiation or with varying doses of radiation to the thorax. Some of the mice were genetically engineered to lack the ICAM-1 gene, while others had a normal ICAM-1 gene. The researchers measured the degree of lung inflammation, fibrosis, and decreased lung performance in the groups of mice.
Lungs of mice that lacked the ICAM-1 gene had markedly fewer infiltrating leukocytes, whose presence indicates inflammation, at all radiation doses compared with the irradiated lungs of normal mice. The lungs of engineered mice also contained less hydroxyproline, a marker of fibrous collagen build-up, than the lungs of normal mice. Moreover, mice lacking ICAM-1 had a lower incidence of respiratory distress and required higher doses of radiation than normal mice to show signs of distress.
In an accompanying editorial, Lisa A. Kachnic, M.D., of the Boston Medical Center, and Simon N. Powell, M.D., Ph.D., of the Massachusetts General Hospital in Boston, point out that loss of ICAM-1 function resulted in only a small increase in radiation tolerance. They say that "although modulation of ICAM-1 may well help improve radiation tolerance of the lungs, it is unlikely to completely prevent lung injury."
However, Kachnic and Powell note that ICAM-1 deficiency could be integrated with other factors affecting radiation-induced lung damage and that future studies looking at these relationships may yield more insight into therapy-induced lung injury.
Editorial: Gina DiGravio, Boston Medical Center, (617) 638-8491, fax: (617) 638-8044, firstname.lastname@example.org
Hallahan DE, Geng L, Shyr Y. Effects of intercellular adhesion moledule-1 (ICAM-1) null mutation on radiation-induced pulmonary fibrosis and respiratory insufficiency in mice. J Natl Cancer Inst 2002;94:733--41.
Editorial: Kachnic LA, Powell SN. Can intercellular adhesion molecule (ICAM) modulation prevent lung injury from ionizing radiation? J Natl Cancer Inst 2002;94:704--5.
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