Carbonic Anhydrase IX and Hypoxia Promote Rat Pulmonary Endothelial Cell Survival during Infection

Lee, Ji Young; Stevens, R.P.; Kash, M.; Alexeyev, Mikhail; Balczon, Ron; Zhou, Chun; Renema, Phoibe; Koloteva, Anna; Kozhukhar, Natalya; Pastukh, Viktor M.; Gwin, M.S.; Voth, S.B.; Deweever, A.; Wagener, Brant M.; Pittet, Jean–François; Eslaamizaad, Yasaman; Siddiqui, Waqar; Nawaz, Talha; Clarke, C. P.; Fouty, Brian; Audia, Jonathon P.; Alvarez, Diego F.; Stevens, Troy

doi:10.1165/rcmb.2020-0537oc

Cited by 2 publications

(1 citation statement)

References 49 publications

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“…Of note, our study was initiated prior to the Sepsis-3 criteria [ 14 ], and therefore, the attending physician utilised the Sepsis-2 criteria to identify individuals for enrolment [ 15 , 16 ]. A summary of patient demographics and clinical data are presented in table 1 , building on a subset of these data that were previously reported [ 17 ]. Of the ICU patients, 14 out of 36 (39%) of the non-septic and 38 out of 77 (49%) of the septic patients also had blood collected at 7 days post-admission (7dp) to the ICU (in two BD Vacutainer™, ThermoFisher #02685125).…”

Section: Methodsmentioning

confidence: 99%

Amyloid-β and caspase-1 are indicators of sepsis and organ injury

Tuckey,

Brandon,

Eslaamizaad

et al. 2023

ERJ Open Res

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BackgroundSepsis is a life-threatening condition that results from a dysregulated host response to infection, leading to organ dysfunction. Despite the prevalence and associated socioeconomic costs, treatment of sepsis remains limited to antibiotics and supportive care, and a majority of intensive care unit (ICU) survivors develop long-term cognitive complications post- discharge. The present study identifies a novel regulatory relationship between amyloid-β (Aβ) and the inflammasome-caspase-1 axis as key innate immune mediators that define sepsis outcomes.MethodsMedical ICU patients and healthy individuals were consented for blood and clinical data collection. Plasma cytokine, caspase-1, and Aβ levels were measured. Data were compared against indices of multi-organ injury and other clinical parameters. Additionally, recombinant proteins were testedin vitroto examine the effect of caspase-1 on a functional hallmark of Aβ, namely aggregation.ResultsPlasma caspase-1 levels displayed the best predictive value in discriminating ICU patients with sepsis from non-infected ICU patients (AUROC=0.7080). Plasma caspase-1 and the 40 amino acid Aβ isoform (Aβx−40) showed a significant positive correlation and Aβx-40associated with organ injury. Additionally, Aβ plasma levels continued to rise from time of ICU admission to 7-days post-admission.In silico, Aβ harbors a predicted caspase-1 cleavage site, andin vitrostudies demonstrated that caspase-1 cleaved Aβ to inhibit its auto-aggregation, suggesting a novel regulatory relationship.ConclusionsAβx-40and caspase-1 are potentially useful early indicators of sepsis and its attendant organ injury. Additionally, Aβx-40has emerged as a potential culprit in the ensuing development of post-ICU-syndrome.

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Section: Methodsmentioning

confidence: 99%

Amyloid-β and caspase-1 are indicators of sepsis and organ injury

Tuckey,

Brandon,

Eslaamizaad

et al. 2023

ERJ Open Res

Self Cite

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Carbonic anhydrase IX proteoglycan-like and intracellular domains mediate pulmonary microvascular endothelial cell repair and angiogenesis

Stevens

Alexeyev

Kozhukhar

et al. 2022

American Journal of Physiology-Lung Cellular and Molecular Phys

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The lungs of patients with acute respiratory distress syndrome (ARDS) have hyperpermeable capillaries that must undergo repair in an acidic microenvironment. Pulmonary microvascular endothelial cells (PMVECs) have an acid-resistant phenotype, in part due to carbonic anhydrase IX (CA IX). CA IX also facilitates PMVEC repair by promoting aerobic glycolysis, migration, and network formation. Molecular mechanisms of how CA IX performs such a wide range of functions are unknown. CA IX is comprised of four domains known as the proteoglycan-like (PG), catalytic (CA), transmembrane (TM), and intracellular (IC) domains. We hypothesized that the PG and CA domains mediate PMVEC pH homeostasis and repair, and the IC domain regulates aerobic glycolysis and PI3k/Akt signaling. The functions of each CA IX domain were investigated using PMVEC cell lines that express either a full-length CA IX protein or a CA IX protein harboring a domain deletion. We found that the PG domain promotes intracellular pH homeostasis, migration, and network formation. The CA and IC domains mediate Akt activation but negatively regulate aerobic glycolysis. The IC domain also supports migration while inhibiting network formation. Finally, we show that exposure to acidosis suppresses aerobic glycolysis and migration, even though intracellular pH is maintained in PMVECs. Thus, we report that 1) The PG and IC domains mediate PMVEC migration and network formation, 2) the CA and IC domains support PI3K/Akt signaling, and 3) acidosis impairs PMVEC metabolism and migration independent of intracellular pH homeostasis.

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Carbonic Anhydrase IX and Hypoxia Promote Rat Pulmonary Endothelial Cell Survival during Infection

Cited by 2 publications

References 49 publications

Amyloid-β and caspase-1 are indicators of sepsis and organ injury

Amyloid-β and caspase-1 are indicators of sepsis and organ injury

Carbonic anhydrase IX proteoglycan-like and intracellular domains mediate pulmonary microvascular endothelial cell repair and angiogenesis

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