Hyporesponsiveness of donor cells to lipopolysaccharide stimulation reduces the severity of experimental idiopathic pneumonia syndrome: Potential role for a gut-lung axis of inflammation

Idiopathic pneumonia syndrome (LPS) is a major complication of allogeneic b one marrow transplantation (BMT), We have shown that experimental IFS is as sociated with increased levels of LPS and TNF-alpha in the bronchoalveolar lavage (BAL) fluid, We hypothesized that the deleterious effects of these i nflammatory mediators in the lung may be linked to gut injury that develops after BMT, To test this hypothesis, we used mouse strains that differ in t heir sensitivity to LPS as donors in an experimental BMT model, Lethally ir radiated C3FeB6F(1) hosts received BMT from either LPS-sensitive or LPS-res istant donors. Five weeks after BMT, LPS-resistant BMT recipients had signi ficantly less lung injury compared with recipients of LPS-sensitive BMT, Th is effect was associated with reductions in TNF-alpha secretion (both in vi tro and in vivo), BAL fluid LPS levels, and intestinal injury. The relation ship between TNF-alpha, gut toxicity, and lung injury was examined further by direct cytokine blockade in vivo; systemic neutralization of TNF-alpha r esulted in a significant reduction in gut histopathology, BAL fluid LPS lev els, and pulmonary dysfunction compared with control-treated animals, We co nclude that donor resistance to endotoxin reduces IFS in this model by decr easing the translocation of LPS across the intestinal border and systemic a nd pulmonary TNF-alpha production. These data demonstrate a potential etiol ogic link between gut and lung damage after BMT and suggest that methods th at reduce inflammatory responses to LPS, and specifically, those that prote ct the integrity of the gut mucosa, may be effective in reducing IFS after BMT.