Amplification Mechanisms of Lung Endothelial Inflammation During Acute Lung Injury

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Jalees  Rehman
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $563,095
Funding agency: National Heart Lung and Blood Institute

PROJECT SUMMARY / ABSTRACT
Lung failure from endotoxemia and sepsis induces widespread and often rapid lung vascular endothelial injury due
to unfettered influx of inflammatory cells such as neutrophils and macrophages. This maladaptive inflammatory
response outpaces the reparative capacity of lungs, resulting in profound inflammatory lung injury and hypoxemia.
This proposal focuses on fundamental amplification mechanisms underlying the maladaptive inflammatory
activation of the lung endothelium. Our central hypothesis is that the inflammatory response to threat signals such
as the initial breaching of the endothelial plasma membrane by bacterial lipopolysaccharide (LPS) and rapid release
of mitochondrial DNA by the injured mitochondria into the cytosol massively and acutely amplifies the inflammatory
response and thus serves as essential feed-forward mechanisms for progression of acute lung injury (ALI). In Aim
1, we will determine the mechanisms by which the recently identified perforin Gasdermin D mediates
endothelial plasma membrane pore formation and the mechanisms of activation of the K+ efflux ion channel
TWIK2 that we have recently identified. We will address the role of amplifying K+ efflux on the severity and
rapidity of endothelial NLRP3 inflammasome activation and fulminant lung injury. In Aim 2, we will define
another crucial amplification mechanism, the potentially important role of Gasdermin D-mediated
mitochondrial (mt) membrane pore formation and the release of mtDNA, which may also catastrophically
amplifiy lung injury via activation of Type I interferon signaling. These mechanistically driven studies will utilize
genetic mouse models (endothelial specific knockout models in our labs) as well as comprehensive imaging,
electrophysiological and physiological approaches and thus provide the framework for identifying novel endothelial
amplification inflammatory mechanisms that induce lung vascular injury and ALI. We will elucidate how these
pathways can be targeted to reduce tissue damage and improve survival.

Terms: <2-photon><Acute><Acute Lung Injury><Acute Pulmonary Injury><Address><Amplifiers><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Bacteria><Bacterial DNA><Bacterial Infections><Beta Proprotein Interleukin 1><Binding><Blood Circulation><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Vessels><Bloodstream><Body Tissues><Caspase><Caspase Gene><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell Survival><Cell Viability><Cell membrane><Cell-Death Protease><Cells><Cessation of life><Complication><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Cytoplasmic Membrane><Cytosol><DNA><DNA Damage><DNA Injury><Data><Death><Deoxyribonucleic Acid><Disease Progression><Electrophysiology><Electrophysiology (science)><Endothelial Cells><Endothelium><Endotoxemia><Genetic><Host Defense><Hypoxemia><ICE-like protease><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Image><Immune><Immune Cell Activation><Immune response><Immune system><Immunes><Immunological response><Infection><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Injury><Interferon Type I><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ion Channel><Ionic Channels><Ions><Knock-out><Knockout><Lead><Lipopolysaccharides><LoxP-flanked allele><Lung><Lung Capacity><Lung Respiratory System><Lung damage><MOF syndrome><Macrophage><Marrow Neutrophil><Mediating><Membrane Channels><Miscellaneous Antibiotic><Mitochondria><Mitochondrial DNA><Modeling><Molecular><Molecular Interaction><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Mφ><N-terminal><NH2-terminal><Natural regeneration><Neurophysiology / Electrophysiology><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Organ><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Pattern><Pb element><Physiologic><Physiological><Plasma Membrane><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Preinterleukin 1 Beta><Proteins><Pulmonary imaging><Regeneration><Regenerative capacity><Research><Role><Sepsis><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stimulator of Interferon Genes><System><Testing><Tissues><Vascular Endothelium><bacteria infection><bacterial disease><biological signal transduction><blood infection><bloodstream infection><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cell regeneration><cellular regeneration><cyclic GMP-AMP synthase/STING><cystein protease><cystein proteinase><cysteine endopeptidase><cytokine><electrophysiological><endothelial regeneration><fighting><floxed><floxed allele><heavy metal Pb><heavy metal lead><host response><hypoxemic><imaging><immune activation><immune system response><immunoresponse><improved><injuries><interventional strategy><intra-vital imaging><intravital imaging><lung failure><lung imaging><lung injury><lung scanning><lung vascular injury><lymphocyte pore-forming protein><microvesicles><mitochondrial><mitochondrial membrane><mortality><mouse model><mtDNA><multiorgan failure><multiple organ system failure><murine model><necrocytosis><neutrophil><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathogen><pathway><perforin><plasmalemma><polymicrobial sepsis><prevent><preventing><programs><pulmonary><pulmonary damage><pulmonary failure><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><pulmonary vascular injury><regenerate><regeneration ability><regeneration capacity><reparative ability><reparative capacity><reparative potential><response><social role><two-photon><vascular><viral DNA><virus DNA>