A mouse model demonstrates a link between transfused UVB irradiated platelets and acute lung injury

Scientists at the U.S. Food and Drug Administration (FDA) have reported that studies performed in animals provide a proof of a concept that transfused UV-light damaged PLTs can mediate lung injury. These studies suggest that patients whose lungs are already inflamed by an underlying condition or cause, could potentially suffer further lung damage if they receive a transfusion of platelets that were exposed to ultraviolet B (UVB) light.

The scientists, at FDA’s Center for Biologics Evaluation and Research (CBER), did the study in response to an observation in a clinical trial that some patients who were transfused with platelets treated with UV light and a photosensitizing chemical to reduce the presence of pathogens (e.g., viruses and bacteria), appeared to be more likely to develop sudden respiratory distress.

Platelets (thrombocytes) are small blood cells that control bleeding by forming clots in damaged blood vessels. People with a low platelet count, such as those who are undergoing chemotherapy for cancer, are at risk of serious bleeding. These patients usually receive many transfusions of platelets; therefore it is important to ensure that these platelets are free of potential pathogens. One way to reduce pathogens is to add a chemical photosensitizer and activate it with UV light. The photosensitizer can bind to nucleic acids (DNA or RNA) of the pathogens and, once activated by the UV light, damage them.

Platelets have only small amounts of nucleic acids and thus should not be affected by the treatment. However, the UV light can damage other parts of the cells. Previously, it was not clear if the platelets damaged by UV light could have adverse effects on the patients or if they would only be quickly removed from circulation.

CBER scientists infused immunodeficient mice (i.e., mice that would not immediately reject human platelets) intravenously with either UVB-treated human platelets, or with platelets that were untreated with UVB. UVB-treated platelets were removed from circulation by the liver cells faster than the untreated platelets. This quick removal from circulation usually means that the platelets are damaged.

CBER scientists then investigated what would happen if UVB-treated platelets were infused into mice treated with a lipid extract from bacteria called lipopolysaccharide (LPS) to mimic certain types of bacterial infections in humans. When the LPS-treated mice were injected with the UVB-treated platelets, the platelets accumulated in the lungs, causing physiologic changes representative of acute lung injury (ALI). However, un-radiated platelets did not accumulate in the lungs of LPS-injected mice and did not cause ALI.

ALI disrupts the lining of the lungs and causes fluid to accumulate in their tiny air sacs, preventing oxygen from passing through the lungs and into the body. In addition to finding increased fluid in the lungs after transfusion of the UVB-treated platelets into the LPS injected mice, the scientists also found that the lung fluid contained abnormally high levels of protein and white blood cells, which are additional signs of such injury.

The findings of the study suggest that UVB irradiation can alter platelets so they accumulate in the lungs of mice, where they trigger lung damage that leads to an increase in fluid and protein in the air sacs.

Injecting UV-irradiated platelets into mice treated with LPS is similar to what can occur in immunosuppressed patients who have a bacterial infection and who could receive pathogen reduced platelet transfusions. Some of the patients may have inflamed lungs from an active infection or chemotherapy.

The fact that the mice in this study developed ALI following treatment with UVB irradiated platelets and LPS is similar to clinical events reported to have occurred in patients transfused with UV treated platelets in a clinical trial suggests that the mice might be undergoing the same response.

Furthermore, the development of a mouse model for studying ALI linked to platelets exposed to UVB light will enable further study of this problem and provide scientists with an animal model to evaluate preventive or therapeutic approaches.

Article

“Ultraviolet B light-exposed human platelets mediate acute lung injury in a two-event mouse model of transfusion”

Transfusion,2011, 51:2343-2357

Authors

Monique P. Gelderman, Xuan Chi, Li Zhi, and Jaroslav G. Vostal

Laboratory of Cellular Hematology, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD.