Systemic lupus erythematosus-associated diffuse alveolar hemorrhage: A case report and review of the literature.

Systemic lupus erythematosus is associated with numerous pleuropulmonary complications. Although uncommon, diffuse alveolar hemorrhage represents a life-threatening cause of acute respiratory failure among patients with lupus. Here, we present a 24-year-old woman with a history of lupus who developed hemoptysis and respiratory failure associated with diffuse radiographic infiltrates and anemia. Bronchoscopy confirmed diffuse alveolar hemorrhage. She was managed with supportive care, plasmapheresis, and immunosuppressive pharmacotherapy leading to sustained resolution of her pulmonary hemorrhage and respiratory failure. We then review the available literature on the pathophysiology and management of lupus-associated diffuse alveolar hemorrhage, which centers on supportive care, reversal of coagulopathy, and immunosuppressive measures.

The Novel mTOR Complex 1/2 Inhibitor P529 Inhibits Human Lung Myofibroblast Differentiation.

Idiopathic pulmonary fibrosis is a progressive and deadly disorder with very few therapeutic options. Palomid 529 (8-(1-hydroxyethyl)-2-methoxy-3-(4-methoxybenzyloxy)-benzo[c]chromen-6-one; P529) is a novel dual inhibitor of mechanistic target of rapamycin complex 1/2 (mTORC1/2). In these studies, we investigated the effect of P529 on TGF-ß-dependent signaling and myofibroblast differentiation. TGF-ß-induced phosphorylation of the mTORC1 targets, p70 S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), were both dose dependently inhibited by P529 in human lung fibroblasts with maximal inhibition occurring between 10 and 20 µM. mTORC2-mediated phosphorylation of Akt at the S473 site was partially inhibited with a similar dose dependency, as was TGF-ß-induced myofibroblast differentiation. Protein levels of TGF-ß-induced fibronectin and collagen were similarly decreased by P529. At this dose, there was also inhibition of mRNA transcript levels for Col1 and α-SMA, suggesting inhibition of transcriptional activation. However, there was no effect of P529 on canonical TGF-ß-induced Smad signaling, as assessed by receptor-associated Smad2/3 phosphorylation, Smad2/3/4 translocation, or Smad-driven gene expression, as assessed by Smad-binding element driven luciferase. Conversely, activation of mTORC1/2 signaling was dependent on TGF-ß type I receptor (ALK5) signaling and on Smad2/3 expression. P529 treatment disrupted TGF-ß-induced actin stress fiber formation during myofibroblast differentiation, the deposition of new extracellular fibronectin matrix, and linear wound closure by fibroblasts. Likewise, mTOR knockdown inhibited TGF-ß-induced myofibroblast differentiation. In conclusion, P529 inhibits TGF-ß-induced myofibroblast differentiation, actin stress fiber formation, and matrix protein expression and deposition. Inhibition of mTORC1/2 by P529 may be a promising approach to inhibit in vivo fibrosis. J. Cell. Biochem. 118: 2241-2249, 2017. © 2017 Wiley Periodicals, Inc.