Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span.

Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

Molecular dynamics simulations of anchored viral peptide interactions.

The authors use molecular dynamics simulations to investigate viral peptide interactions as the cause of pH-dependent fusion in liposomal drug delivery. Viral peptides (LEFN) are composed of a linker peptide (LELELELE) connected to a synthetic viral peptide (DRGWGNGCGLFGKGSI). Rather than being anchored in a lipid bilayer, the viral peptides are anchored to a neutral surface by the amino termini of the linker peptide (anchor atoms are mobile in the xy-plane). Atomistic-level peptide pair arrangement on a surface depends on pH; however, the overall propensity to cluster is independent of pH, indicating that pH-sensitive liposome fusion is not due to peptide clustering. To further investigate a molecular cause of pH-sensitive fusion, the authors treat the linker peptides as ectodomains, with the assumption that the viral peptides are already inserted into a target membrane. In these simulations, the linker peptides are elongated to encourage them to bundle. At both high and low pH, the peptides readily bundle. At high pH, however, bundling was constrained by long-range order induced by sodium ions bridging negatively charged glutamic acid residues on neighboring peptides. The authors hypothesize that this constraint hinders the ability of the linker peptides to support viral peptide insertion, resulting in decreased levels of fusion observed experimentally.

Structural effects and translocation of doxorubicin in a DPPC/Chol bilayer: the role of cholesterol.

We use molecular dynamics simulations to characterize the influence of cholesterol (Chol) on the interaction between the anticancer drug doxorubicin (DOX) and a dipalmitoyl phosphatidylcholine/Chol lipid bilayer. We calculate the potential of mean force, which gives us an estimate of the free energy barrier for DOX translocation across the membrane. We find free energy barriers of 23.1 ± 3.1 k(B)T, 36.8 ± 5.1 k(B)T, and 54.5 ± 4.7 k(B)T for systems composed of 0%, 15%, and 30% Chol, respectively. Our predictions agree with Arrhenius activation energies from experiments using phospholipid membranes, including 20 k(B)T for 0% Chol and 37.2 k(B)T for 20% Chol. The location of the free energy barrier for translocation across the bilayer is dependent on composition. As Chol concentration increases, this barrier changes from the release of DOX into the water to flip-flop over the membrane center. The drug greatly affects local membrane structure by attracting dipalmitoyl phosphatidylcholine headgroups, curving the membrane, and allowing water penetration. Despite its hydrophobicity, DOX facilitates water transport via its polar groups.