No abstract

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 vasopressin (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 less than 0.01-P less than 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 less than 0.001), which resulted in markedly elevated lavage cell numbers and protein content as well as edema formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Resolution of alveolar edema depends on clearance of serum protein, as well as liquid from the alveolar space. Protein clearance is slower than liquid clearance and may take days to weeks. Our earlier studies presented evidence for the importance of paracellular removal of soluble protein from the air spaces. However, long-term protein clearance may also depend on uptake by alveolar epithelial cells or macrophages. This study examined cellular uptake of soluble human albumin and insoluble colloidal gold-albumin from the lungs of anesthetized rabbits. Native albumin was endocytosed by both alveolar type I and type II cells and appeared in vesicles and endosomes. Neither cell type took up colloidal gold-albumin over periods as long as 8 h. Alveolar macrophages took up native albumin and colloidal gold-albumin to a greater extent and more rapidly than alveolar epithelial cells. The tracer proteins were found in vesicles, endosomes, and phagolysosomes. Similarly, cultured alveolar macrophages took up native albumin more rapidly than cultured type II cells. Thus macrophages may be important in clearing precipitated protein from the air spaces, and they may have a role in completing the clearance of soluble protein. The potential for transepithelial transport of soluble alveolar protein exists, but based on this work and our prior studies, it appears to be a low-capacity pathway.

The passage from the lower respiratory tract into the blood of human GH (hGH; M(r) = 22,000) and bovine serum albumin (BSA; M(r) = 67,000) was assessed after intratracheal instillation in adult rats. The plasma level of immunoreactive hGH reached its maximum at 0.5-1 h after instillation and had almost disappeared within 24 h. Higher plasma levels were obtained in male rats than in female rats resulting in a higher total lung passage of hGH in male rats than in female rats (means +/- S.D.; 6.0 +/- 1.7% vs 3.3 +/-1.2%, P<0.01). The plasma level of BSA showed a different pattern, with a maximum at 16-24 h after instillation and a total lung passage of 4.3 +/- 1.7% of the given dose for both sexes. The plasma levels of hGH increased nonlinearly with increasing dose instilled in the dose range 36-720 micrograms/kg body weight. When hGH was instilled daily at a dose of 720 micrograms/kg body weight to hypophysectomized rats for 1 week, they responded with a significant increase in body weight when compared with hypophysectomized control rats (16.8 +/- 4.2 g vs -1.8 +/- 2.4 g, P<0.001). The results demonstrate that, despite their different molecular weights, hGH and BSA pass through the lower respiratory tract into the circulation with similar efficiencies in the rat. However, the lung passage of hGH, unlike that of BSA, showed sexual dependency, an earlier plasma concentration maximum and a tendency of the passage to saturation with increasing dose instilled.(ABSTRACT TRUNCATED AT 250 WORDS)

The degradation of the vasopressin analogue dDAVP was studied by reversed phase high-performance liquid chromatography (HPLC) after incubations in pancreatic juice and intestinal mucosa homogenates. dDAVP remained stable in pancreatic juice for a period of 60 min. while the parent hormone arginine vasopressin (AVP) was completely degraded within 5 min. In intestinal mucosa homogenates dDAVP was degraded with half-lives of 9 min. (fast phase) and 161 min. (slow phase), about four times slower than AVP. By amino-acid analysis it was confirmed that the metabolite [Mpa1, Des-D-Arg8-Gly9 NH2]-vasopressin was gradually produced. No other breakdown products were observed. These findings may be of value for the further development of more stable peptide analogues which may be effective upon oral administration.