Severe pulmonary pathology after intravenous administration of vectors in cirrhotic rats.
After an intravascular injection, adenoviral vectors are normally taken up by the reticuloendothelial system in the liver, where they rapidly trigger an innate response. However, we have previously found that the biodistribution of adenoviral vectors is altered in cirrhotic rats due to the presence of pulmonary intravascular macrophages, which cause a shift in vector uptake from the liver to the lungs. We now report that this is correlated with fatal pulmonary hemorrhagic edema in cirrhotic rats. In addition, cirrhotic rats reacted to vector with enormous increases in TNF-alpha and IL-6 and markedly prolonged coagulation times. Although we also saw fatal reactions to high doses of adenoviral vectors in normal rats, the time course and symptoms were very different, and pulmonary hemorrhagic edema was seen only in cirrhotic rats. Because abnormal pulmonary reticuloendothelial uptake is known to occur in humans during cirrhosis and other diseases, there is the potential that intravascular administration of adenoviral vectors might cause lung pathology in such patients.
Smith
Jeffrey S
JS
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Tian
Jie
J
Lozier
Jay N
JN
Byrnes
Andrew P
AP
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000633:toxicity*; D006470:Hemorrhage / Q000209:etiology; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000150:complications*; D008168:Lung / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000502:physiology; D012157:Mononuclear Phagocyte System / Q000503:physiopathology; D011516:Prothrombin / Q000032:analysis; D011654:Pulmonary Edema / Q000209:etiology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013925:Thromboplastin / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D011516:Prothrombin; D013925:Thromboplastin