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1.  Monocytes Recruited to the Lungs of Mice during Immune Inflammation Ingest Apoptotic Cells Poorly 
Apoptotic cells must be cleared to resolve inflammation, but few resident alveolar macrophages (AMø) from normal lungs ingest apoptotic cells. We examined how Mø ingestion of apoptotic cells is altered during immune inflammation induced by intratracheal challenge of primed C57BL/6 mice using sheep red blood cells. Resident AMø were labeled in situ before challenge using intravenous PKH26 to distinguish them from recruited monocytes. Using flow cytometry, we identified phagocytosis of fluorescently-labeled apoptotic thymocytes by alveolar mononuclear phagocytes in vitro and in vivo, and measured surface molecule expression. Intratracheal challenge induced rapid recruitment of monocytes, peaking at Day 3 and decreasing thereafter, whereas numbers of resident AMø did not change significantly. At all times, the percentage of phagocytes ingesting apoptotic thymocytes in vitro was greater among resident AMø (28–45%) than among recruited monocytes (9–19%), but was low in both cell types relative to ingestion of immunoglobulin-opsonized targets. There was also a nonsignificant trend toward lower ingestion by monocytes in vivo. MerTK, a receptor tyrosine kinase crucial for apoptotic cell phagocytosis, was expressed by resident AMø, but not by recruited monocytes. Relative to resident AMø, monocytes recruited to the alveolus ingest apoptotic cells meagerly, possibly due to absence of MerTK expression.
doi:10.1165/rcmb.2004-0108OC
PMCID: PMC2267037  PMID: 15563692
apoptosis; adhesion molecules; mice; inbred strains; macrophage; receptor tyrosine kinase
2.  Prostaglandin E2 Inhibits Fibroblast Migration by E-Prostanoid 2 Receptor–Mediated Increase in PTEN Activity 
An increased migratory phenotype exists in lung fibroblasts derived from patients with fibroproliferative lung disease. Prostaglandin E2 (PGE2) suppresses fibroblast migration, but the receptor(s) and mechanism(s) mediating this action are unknown. Our data confirm that treatment of human lung fibroblasts with PGE2 inhibits migration. Similar effects of butaprost, an E-prostanoid (EP) 2 receptor–specific ligand, implicate the EP2 receptor in migration-inhibitory signaling. Further, migration in fibroblasts deficient for the EP2 receptor cannot be inhibited by PGE2 or butaprost, confirming the central role of EP2 in mediating these effects. Our previous data suggested that phosphatase and tensin homolog on chromosome ten (PTEN), a phosphatase that opposes the actions of phosphatidylinositol-3-kinase (PI3K), may be important in regulating lung fibroblast motility. We now report that both PGE2 and butaprost increase PTEN phosphatase activity, without a concomitant increase in PTEN protein levels. This contributes to EP2-mediated migration inhibition, because migration in PTEN-null fibroblasts is similarly unaffected by EP2 receptor signaling. Increased PTEN activity in response to EP2 stimulation is associated with decreased tyrosine phosphorylation on PTEN, a mechanism known to regulate enzyme activity. Collectively, these data describe the novel mechanistic finding that PGE2, via the EP2 receptor, decreases tyrosine phosphorylation on PTEN, resulting in increased PTEN enzyme activity and inhibition of fibroblast migration.
doi:10.1165/rcmb.2004-0126OC
PMCID: PMC1965457  PMID: 15539459
fibroblast; eicosanoid; phosphatase; cell migration

Results 1-2 (2)