title: Frontline Science: D1 dopaminergic receptor signaling activates the AMPK-bioenergetic pathway in macrophages and alveolar epithelial cells and reduces endotoxin-induced ALI.
abstract: Catecholamines, including β-adrenergic and dopaminergic neurotransmitters, have an essential role in regulating the "fight or flight" reflex and also affects immune cell proinflammatory action. However, little is known about whether catecholamines prevent dysfunction of metabolic pathways associated with inflammatory organ injury, including development of acute lung injury (ALI). We hypothesize that selected catecholamines may reduce metabolic alterations in LPS-stimulated macrophages and in the lungs of mice subjected to endotoxin-induced ALI, a situation characterized by diminished activity of AMP-activated protein kinase (AMPK). We found that activation of the dopamine 1 receptor (D1R) with fenoldopam, but not stimulation of adrenergic receptors with norepinephrine, resulted in a robust activation of AMPK in peritoneal macrophages, human monocytes, or alveolar epithelial cells (AECs). Such AMPK activation was mediated by a phospholipase C (PLC)-dependent mechanism. Unlike norepinephrine, D1R activation also prevented Thr172-AMPK dephosphorylation and kinase inactivation in LPS-treated macrophages. Furthermore, we show that a culture of AECs with either fenoldopam or the AMPK activator metformin effectively diminished IL-1β-induced release of adverse paracrine signaling, which promotes the macrophage proinflammatory response. In vivo, fenoldopam reduced the severity of LPS-induced ALI, including development of pulmonary edema, lung permeability, and production of inflammatory cytokines TNF-α, MIP-2, or KC and HMGB1. Fenoldopam also prevented AMPK dephosphorylation in the lungs of LPS-treated mice and prevented loss of mitochondrial complexes NDUFB8 (complex I) and ATP synthase (complex V). Collectively, these results suggest that dopamine is coupled to AMPK activation, which provides a substantial anti-inflammatory and bioenergetic advantage and reduces the severity of endotoxin-induced ALI.
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, Alabama, USA; and.
authors.forename: Nathaniel B
authors.initials: NB
authors.lastname: Bone
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, Alabama, USA; and.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pittet
authors.affiliation: Department of Medicine, University of Alabama, Birmingham, Alabama, USA; and zmijewsk@uab.edu.
authors.forename: Jaroslaw W
authors.initials: JW
authors.lastname: Zmijewski
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004579:Electron Transport / Q000187:drug effects; D004731:Endotoxins; D004734:Energy Metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018818:Fenoldopam / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D019899:Paracrine Communication / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011941:Receptors, Adrenergic / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D011941:Receptors, Adrenergic; D017447:Receptors, Dopamine D1; D055372:AMP-Activated Protein Kinases; D010738:Type C Phospholipases; D018818:Fenoldopam
keywords: ARDS; LPS; catecholamines; dopamine; immune homeostasis; pulmonary