LUNG TO BLOOD PASSAGE OF DIFFERENT-SIZED MOLECULES DURING LUNG INFLAMMATION IN THE RAT

The passage of different-sized marker molecules over the lower respiratory tract into the blood circulation during pulmonary inflammation induced by dextran, endotoxin [i.e., lipopolysaccharide from Escherichia coli (LPS)], or ferritin was assessed in the rat. Bovine immunoglobulin G (BigG, mol wt = 150,000 Da), bovine serum albumin (BSA, mol wt = 67,000 Da), and the nonapeptide 1-deaminocysteine-8-D-arginine vasopression (dDAVP, mol wt = 1,067 Da) were used as permeability markers after intratracheal instillation. The pathophysiological indexes of a proceeding lung inflammation were increased total cell number, changed leukocyte proportions and increased total protein content obtained in bronchoalveolar lavage, and lung edema formation shown as an increased lung wet-dry weight difference. Intratracheal instillation of dextran induced a moderate neutrophil invasion into the lungs but had no effect on the passage of the different markers over the lungs (BIgG 1.8 +/- 0.6%, BSA 3.5 +/- 1.2%, dDAVP 26.1 +/- 20.7%) compared with control rats instilled with the markers alone (1.8 +/- 0.4%, 4.1 +/- 1.3%, 20.0 +/- 3.8%, respectively). Endotoxin administration resulted in markedly higher lavage cell counts and lung edema concomitantly with an increased lung passage of the markers (3.2 +/- 0.9%, 22.0 +/- 6.1%, 33.3 +/- 12.0%, respectively; P < 0.01-P < 0.001). The highest marker passage was obtained when the inflammation was most severe, i.e., after ferritin administration (17.6 +/- 2.3%, 60.0 +/- 6.7%, 41.6 +/- 6.9%, respectively; P < 0.001), which resulted in markedly elevated lavage cell numbers and protein content as well as edema formation. Results from experiments where the iron chelator desferrioxamine (Desferal) was administered together with ferritin suggest that iron released from ferritin plays a crucial role in the observed changes in the lung passage, as a significant decrease in the lung transfer was observed in these rats (11.9 +/- 7.1%, 26.4 +/- 5.0%, 15.2 +/- 5.5%, respectively; P < 0.01-P < 0.001) compared with ferritin-exposed rats. These results show that the inward lung passage of different-sized marker molecules was increased during inflammatory conditions apparently correlated to the severity of the lung injury.