Progressive, irreversible
fibrosis is one of the most clinically significant consequences of ionizing radiation on normal tissue. When applied to lungs, it leads to a complication described as idiopathic
pneumonia syndrome (IPS) and eventually to organ
fibrosis. For its high mortality, the condition precludes treatment with high doses of radiation. There is widespread interest to understand the pathogenetic mechanisms of IPS and to find drugs effective in the prevention of its development. This report summarizes our experience with the protective effects of L 158,809, an
angiotensin II (ANG II) receptor blocker, and two
angiotensin converting enzyme (
ACE) inhibitors in the development of IPS and the role of
transforming growth factor beta (
TGF-beta) and of alpha-
actomyosin (alpha SMA) in pathogenesis of radiation induced
pulmonary fibrosis in an experimental model of bone marrow transplant (BMT). Male WAG/Riji/MCV rats received total body irradiation and a regimen of
cyclophosphamide (CTX) in preparation for bone marrow transplant. While one group of animals remained untreated, the remainders were subdivided into three groups, each of them receiving either the ANG II receptor blocker or one of the two
ACE inhibitors (
Captopril or
Enalapril). Each of the three drugs was administered orally from 11 days before the transplant up to 56 days post transplant. At sacrifice time the irradiated rats receiving only CTX showed a chronic
pneumonitis with septal
fibrosis and
vasculitis affecting, in particular, small caliber pulmonary arteries and arterioles. Their lung content of
hydroxyproline was also markedly elevated in association with the lung concentrations of
thromboxane (TXA2) and
prostaglandin (PGI(2)), (two markers of pulmonary endothelial damage). A significant increase of alpha
actomyosin staining was observed in vessels, septa and macrophages of the same animals which also overexpressed
TGF-beta. When L 158,809,
Captopril and
Enalapril were added to the radiation and
cytoxan treatment, a significant amelioration of the histological damage as well as the overexpression of alpha SMA was observed. Lung concentrations of
hydroxyproline, PGI(2), TXA2 and
TGF-beta were also observed in these animals so that the values of these compounds were closer to those measured in untreated control rats than to their irradiated and
cytoxan treated counterparts.
Angiotensin II plays an important role in the regulation of
TGF-beta and alpha SMA, two
proteins involved in the pathogenesis of
pulmonary fibrosis. The finding that
ACE inhibitors or ANG II receptor blockers protect the lungs from radiation induced
pneumonitis and
fibrosis reaffirms the role that ANG II plays in this inflammatory process and suggests an additional indication of treatment of this condition, thus opening a new potential pharmacologic use of these drugs.