6 research outputs found
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Adipose-derived stem cells weigh in as novel therapeutics for acute lung injury
Acute lung injury is characterized by intense neutrophilic lung inflammation and increased alveolar-capillary barrier permeability leading to severe hypoxemia, and is associated with high mortality despite improvements in supportive care. There is an urgent need for effective therapies for acute lung injury. Zhang and colleagues tested the efficacy of adipose-derived stem cells in acute lung injury in mice. When adipose-derived stem cells were delivered to mice that had been challenged with lipopolysaccharide, they potently limited acute lung inflammation and injury in the mice, indicating that adipose-derived stem cells have therapeutic potential in acute lung injury in humans. Herein, we discuss the advantages and potential limitations of using adipose-derived stem cells as therapeutics for human acute lung injury
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Folliculin regulates cellâcell adhesion, AMPK, and mTORC1 in a cellâtypeâspecific manner in lungâderived cells
Abstract Germline lossâofâfunction BHD mutations cause cystic lung disease and hereditary pneumothorax, yet little is known about the impact of BHD mutations in the lung. Folliculin (FLCN), the product of the BirtâHoggâDube (BHD) gene, has been linked to altered cellâcell adhesion and to the AMPK and mTORC1 signaling pathways. We found that downregulation of FLCN in human bronchial epithelial (HBE) cells decreased the phosphorylation of ACC, a marker of AMPK activation, while downregulation of FLCN in small airway epithelial (SAEC) cells increased the activity of phosphoâS6, a marker of mTORC1 activation, highlighting the cell typeâdependent functions of FLCN. Cellâcell adhesion forces were significantly increased in FLCNâdeficient HBE cells, consistent with prior findings in FLCNâdeficient human kidneyâderived cells. To determine how these altered cellâcell adhesion forces impact the lung, we exposed mice with heterozygous inactivation of Bhd (similarly to humans with germline inactivation of one BHD allele) to mechanical ventilation at high tidal volumes. Bhd+/â mice exhibited a trend (P = 0.08) toward increased elastance after 6 h of ventilation at 24 cc/kg. Our results indicate that FLCN regulates the AMPK and mTORC1 pathways and cellâcell adhesion in a cell typeâdependent manner. FLCN deficiency may impact the physiologic response to inflationâinduced mechanical stress, but further investigation is required. We hypothesize that FLCNâdependent effects on signaling and cellular adhesion contribute to the pathogenesis of cystic lung disease in BHD patients
ADAM9 Is a Novel Product of Polymorphonuclear Neutrophils:Regulation of Expression and Contributions to Extracellular Matrix Protein Degradation during Acute Lung Injury
A disintegrin and a metalloproteinase domain 9 (ADAM9) is known to be expressed by monocytes and macrophages. Herein, we report that ADAM9 is also a product of human and murine polymorphonuclear neutrophils (PMNs). ADAM9 is not synthesized de novo by circulating PMNs. Rather, ADAM9 protein is stored in the gelatinase and specific granules and the secretory vesicles of human PMNs. Unstimulated PMNs express minimal quantities of surface ADAM9, but activation of PMNs with degranulating agonists rapidly (within 15 min) increases PMN surface ADAM9 levels. Human PMNs produce small quantities of soluble forms of ADAM9 (sADAM9). Surprisingly, ADAM9 degrades several extracellular matrix (ECM) proteins including fibronectin, entactin, laminin, and insoluble elastin as potently as MMP-9. However, ADAM9 does not degrade types I, III, or IV collagen, or denatured collagens in vitro. To determine whether Adam9 regulates PMN recruitment or ECM protein turnover during inflammatory responses, we compared wild type (WT) and Adam9(â/â) mice in bacterial lipopolysaccharide (LPS)- and bleomycin-mediated acute lung injury (ALI). Adam9 lung levels increase 10-fold during LPS-mediated ALI in WT mice (due to increases in leukocyte-derived Adam9), but Adam9 does not regulate lung PMN (or macrophage) counts during ALI. Adam9 increases mortality, promotes lung injury, reduces lung compliance, and increases degradation of lung elastin during LPS- and/or bleomycin-mediated ALI. Adam9 does not regulate collagen accumulation in the bleomycin-treated lung. Thus, ADAM9 is expressed in an inducible fashion on PMN surfaces where it degrades some ECM proteins, and promotes alveolar-capillary barrier injury during ALI in mice