A5055035755- Ion Transport and Channel Regulation
- Neonatal Respiratory Health Research
- Pancreatic function and diabetes
- Ion channel regulation and function
- Cancer, Hypoxia, and Metabolism
- Neuroscience of respiration and sleep
- Respiratory Support and Mechanisms
- Hormonal Regulation and Hypertension
- Nitric Oxide and Endothelin Effects
- Muscle Physiology and Disorders
- Metabolism, Diabetes, and Cancer
- Immune Response and Inflammation
- Ubiquitin and proteasome pathways
- Estrogen and related hormone effects
- interferon and immune responses
- Hormonal and reproductive studies
- Mitochondrial Function and Pathology
- Receptor Mechanisms and Signaling
- Adipose Tissue and Metabolism
- Autophagy in Disease and Therapy
- Cellular transport and secretion
- Erythrocyte Function and Pathophysiology
- Medical Imaging and Pathology Studies
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
Northwestern University
2015-2024
Pulmonary and Critical Care Associates
2006-2014
Pulmonary Associates
1988-2010
Midwestern University
2007
Technion – Israel Institute of Technology
2004-2006
Utrecht University
2006
University Medical Center Utrecht
2006
University of Chicago
2006
University of Houston
2006
Karolinska Institutet
2006
Abstract Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood air. 2 (AT2) serve as a partially committed stem cell population, producing AT1 during postnatal alveolar development repair after influenza A SARS-CoV-2 pneumonia 1–6 . Little is known about metabolic regulation of fate lung cells. Here we report that deleting mitochondrial electron transport chain complex I subunit Ndufs2 in mouse gestation led death development. Affected...
During ascent to high altitude and pulmonary edema, the alveolar epithelial cells (AEC) are exposed hypoxic conditions. Hypoxia inhibits fluid reabsorption decreases Na,K-ATPase activity in AEC. We report here that exposure of AEC hypoxia induced a time-dependent decrease parallel number α1 subunits at basolateral membrane (BLM), without changing its total cell protein abundance. These effects were reversible upon reoxygenation specific, because plasma GLUT1 did not response hypoxia. caused...
Patients with acute lung injury develop hypoxia, which may lead to dysfunction and aberrant tissue repair. Recent studies have suggested that epithelial-mesenchymal transition (EMT) contributes pulmonary fibrosis. We sought determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). found induced the expression of alpha-smooth muscle actin (alpha-SMA) vimentin decreased E-cadherin transformed primary human, rat, mouse AEC, suggesting AEC. Both severe moderate EMT. The reactive...
Hypercapnia (elevated CO2 levels) occurs as a consequence of poor alveolar ventilation and impairs fluid reabsorption (AFR) by promoting Na,K-ATPase endocytosis. We studied the mechanisms regulating CO2-induced endocytosis in epithelial cells (AECs) dysfunction rats. Elevated levels caused rapid activation AMP-activated protein kinase (AMPK) AECs, key regulator metabolic homeostasis. Activation AMPK was mediated CO2-triggered increase intracellular Ca2+ concentration...
To maintain cellular ATP levels, hypoxia leads to Na,K-ATPase inhibition in a process dependent on reactive oxygen species (ROS) and the activation of AMP-activated kinase α1 (AMPK-α1). We report here that during AMPK does not require liver B1 (LKB1) but requires release Ca2+ from endoplasmic reticulum (ER) redistribution STIM1 ER-plasma membrane junctions, leading calcium entry via release-activated (CRAC) channels. This increase intracellular induces Ca2+/calmodulin-dependent β...
In patients with acute respiratory failure, gas exchange is impaired due to the accumulation of fluid in lung airspaces. This life-threatening syndrome treated mechanical ventilation, which adjusted maintain exchange, but can be associated carbon dioxide lung. Carbon (CO2) a by-product cellular energy utilization and its elimination affected via alveolar epithelial cells. Signaling pathways sensitive changes CO2 levels were described plants neuronal mammalian However, it has not been fully...
Hypoxia promotes Na,K-ATPase endocytosis via protein kinase C zeta (PKC zeta)-mediated phosphorylation of the alpha subunit. Here, we report that hypoxia leads to 5'-AMP-activated (AMPK) at Thr172 in rat alveolar epithelial cells. The overexpression a dominant-negative AMPK subunit (AMPK-DN) construct prevented hypoxia-induced Na,K-ATPase. reactive oxygen species (ROS) scavenger catalase activation. Moreover, failed activate mitochondrion-deficient rho(0)-A549 cells, suggesting mitochondrial...
We set out to determine whether cellular hypoxia, via mitochondrial reactive oxygen species, promotes Na,K-ATPase degradation the ubiquitin-conjugating system. Cells exposed 1.5% O 2 had a decrease in activity and consumption. The total cell pool of α1 protein decreased on exposure for 30 hours, whereas plasma membrane was 50% degraded after hours which prevented by lysosome proteasome inhibitors. When Chinese hamster ovary cells that exhibit temperature-sensitive defect E1 ubiquitin...
The purpose of this study was to define mechanisms by which dopamine (DA) regulates the Na,K-ATPase in alveolar epithelial type 2 (AT2) cells. activity increased twofold cells incubated with either 1 μM DA or a dopaminergic D agonist, fenoldopam, but not agonist quinpirole. increase paralleled an α1 and β1 protein abundance basolateral membrane (BLM) AT2 This mediated exocytosis Na,K-pumps from late endosomal compartments into BLM. Down-regulation diacylglycerol-sensitive types kinase C...
Significance Exposure to hypoxia requires adaptive mechanisms for survival. During acute hypoxia, Na,K-ATPase endocytosis in alveolar epithelial cells occurs via protein kinase C zeta (PKCζ) phosphorylation of α 1 -Na,K-ATPase independently the hypoxia-inducible factor (HIF). However, exaggerated down-regulation leads cell death. Here we report that during prolonged plasma membrane levels were maintained at ∼50% normoxic values due HIF-mediated up-regulation HOIL-1L, which targets PKCζ...
Abstract Muscle dysfunction is common in patients with adult respiratory distress syndrome and associated morbidity that can persist for years after discharge. In a mouse model of severe influenza A pneumonia, we found the proinflammatory cytokine IL-6 was necessary development muscle dysfunction. Treatment Food Drug Administration–approved Ab antagonist to IL-6R (tocilizumab) attenuated severity A–induced cultured myotubes, promoted degradation via JAK/STAT, FOXO3a, atrogin-1 upregulation....
Abstract Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza COVID-19. In a study of A pneumonia mice, young mice fully recovered from sarcopenia, while older did not. We identified population tissue-resident skeletal muscle macrophages that form spatial niche with satellite cells myofibers but are lost age. Mice gain-of-function mutation Mertk receptor maintained this macrophage-myofiber interaction during...
Hypoxia impairs alveolar fluid reabsorption by promoting Na,K-ATPase endocytosis, from the plasma membrane of epithelial cells. The present study was designed to determine whether hypoxia induces endocytosis via reactive oxygen species (ROS)-mediated RhoA activation. In A549 cells, activation occurred within 15 minutes cells exposure hypoxia. This inhibited in infected with adenovirus coding for gluthatione peroxidase (an H2O2 scavenger), mitochondria depleted (rho0) or expressing decreased...
Hypercapnia has been shown to impair alveolar fluid reabsorption (AFR) by decreasing Na,K‐ATPase activity. Extracellular signal‐regulated kinase pathway (ERK) is activated under conditions of cellular stress and known regulate the Na,K‐ATPase. Here, we show that hypercapnia leads ERK activation in a time‐dependent manner epithelial cells (AEC). Inhibition U0126 or siRNA prevented both hypercapnia‐induced endocytosis impairment AFR. Moreover, inhibition AMPK activation, modulator endocytosis....
The zinc finger transcription factor Miz1 is a negative regulator of TNFalpha-induced JNK activation and cell death through inhibition TRAF2 K63-polyubiquitination in transcription-independent manner. Upon TNFalpha stimulation, undergoes K48-linked polyubiquitination proteasomal degradation, thereby relieving its inhibition. However, the underling regulatory mechanism not known. Here, we report that HECT-domain-containing Mule E3 ligase catalyzes polyubiquitination. Miz1-associated protein...
Elevated CO(2) levels (hypercapnia) occur in patients with respiratory diseases and impair alveolar epithelial integrity, part, by inhibiting Na,K-ATPase function. Here, we examined the role of c-Jun N-terminal kinase (JNK) signaling mammalian cells as well diptera, nematodes rodent lungs. In cells, elevated rapidly induced activation JNK leading to downregulation dysfunction. Hypercapnia-induced required AMP-activated protein (AMPK) C-ζ subsequent phosphorylation at Ser-129. Importantly,...
Epithelial polyploidization after injury is a conserved phenomenon recently shown to improve barrier restoration during wound healing. Whether lung can induce alveolar epithelial polyploidy not known. We show that bleomycin induces type 2 cell (AT2) hypertrophy and polyploidy. AT2 also seen in short term ex vivo cultures, where AT2-to-AT1 transdifferentiation associated with substantial binucleation due failed cytokinesis. Both hypertrophic polyploid features of cells be attenuated by...