Objective: Dipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19.
Design: Phase 2a randomised, placebo-controlled, double-blinded, trial.
Pyroptosis is a form of regulated cell death that is mediated by the membrane-targeting, pore-forming gasdermin family of proteins. Pyroptosis was initially described as a caspase 1- and inflammasome-dependent cell death pathway typified by the loss of membrane integrity and the secretion of cytokines such as IL-1β. However, gasdermins are now recognized as the principal effectors of this form of regulated cell death; activated gasdermins insert into cell membranes, where they form pores that result in the secretion of cytokines, alarmins and damage-associated molecular patterns and cause cell membrane rupture.
View Article and Find Full Text PDFThe lung naturally resists () in healthy individuals, but multiple conditions can disrupt this resistance, leading to lethal invasive infections. Core processes of natural resistance and its breakdown are undefined. We investigated three distinct conditions predisposing to lethal aspergillosis-severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, influenza A viral pneumonia, and systemic corticosteroid use-in human patients and murine models.
View Article and Find Full Text PDFThe mechanisms that drive leukocyte recruitment to the kidney are incompletely understood. Dipeptidase-1 (DPEP1) is a major neutrophil adhesion receptor highly expressed on proximal tubular cells and peritubular capillaries of the kidney. Renal ischemia reperfusion injury (IRI) induces robust neutrophil and monocyte recruitment and causes acute kidney injury (AKI).
View Article and Find Full Text PDFDexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone.
View Article and Find Full Text PDFAbsent in melanoma-2 (AIM2) is an inflammasome-forming innate immune sensor for dsDNA but also exhibits inflammasome-independent functions such as restricting cellular proliferation. AIM2 is expressed in the kidney, but its localization and function are not fully characterized. In normal human glomeruli, AIM2 localized to podocytes.
View Article and Find Full Text PDFThe pryin domain (PYD) domain is involved in protein interactions that lead to assembly of immune-sensing complexes such as inflammasomes. The repertoire of PYD-containing genes expressed by a cell type arms tissues with responses against a range of stimuli. The transcriptional regulation of the PYD gene family however is incompletely understood.
View Article and Find Full Text PDFHuman biological specimen (biospecimen) donation is routinely requested for clinical care and research purposes. Successfully engaging patients and research participants in biospecimen donation depends on what they understand these initiatives entail, including their perceptions of risk. Human biospecimens are stored in facilities routinely referenced as biobanks or biorepositories, both of which labels are known to embody a variety of connotations.
View Article and Find Full Text PDFThe innate immune system responds to infections that give rise to pain. How the innate immune system interacts with the sensory nervous system and contributes to pain is poorly understood. Here we report that hyperactivity of innate immunity primes and initiates pain states via the TLR2-interleukin-33 (IL-33) axis.
View Article and Find Full Text PDFAntibiotic-resistant superbug bacteria represent a global health problem with no imminent solutions. Here we demonstrate that the combination (termed AB569) of acidified nitrite (A-NO) and Na-EDTA (disodium ethylenediaminetetraacetic acid) inhibited all Gram-negative and Gram-positive bacteria tested. AB569 was also efficacious at killing the model organism in biofilms and in a murine chronic lung infection model.
View Article and Find Full Text PDFIntroduction: Diabetic nephropathy (DN) and hypertensive nephrosclerosis (HN) represent the most common causes of chronic kidney disease (CKD) and many patients progress to -end-stage renal disease. Patients are treated primarily through the management of cardiovas-cular risk factors and hypertension; however patients with HN have a more favorable outcome. A noninvasive clinical approach to separate these two entities, especially in hypertensive patients who also have diabetes, would allow for targeted treatment and more appropriate resource allocation to those patients at the highest risk of CKD progression.
View Article and Find Full Text PDFA hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs.
View Article and Find Full Text PDFAbnormal cardiac electrical activity is a common side effect caused by unintended block of the promiscuous drug target human -related gene (hERG1), the pore-forming domain of the delayed rectifier K channel in the heart. hERG1 block leads to a prolongation of the QT interval, a phase of the cardiac cycle that underlies myocyte repolarization detectable on the electrocardiogram. Even newly released drugs such as heart-rate lowering agent ivabradine block the rapid delayed rectifier current I, prolong action potential duration, and induce potentially lethal arrhythmia known as torsades de pointes.
View Article and Find Full Text PDFInflammasomes are multiprotein innate immune complexes that regulate caspase-dependent inflammation and cell death. Pattern recognition receptors, such as nucleotide-binding oligomerization domain (NOD)-like receptors and absent in melanoma 2 (AIM2)-like receptors, sense danger signals or cellular events to activate canonical inflammasomes, resulting in caspase 1 activation, pyroptosis and the secretion of IL-1β and IL-18. Non-canonical inflammasomes can be activated by intracellular lipopolysaccharides, toxins and some cell signalling pathways.
View Article and Find Full Text PDFMucoid mucA22 Pseudomonas aeruginosa (PA) is an opportunistic lung pathogen of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients that is highly sensitive to acidified nitrite (A-NO2-). In this study, we first screened PA mutant strains for sensitivity or resistance to 20 mM A-NO2- under anaerobic conditions that represent the chronic stages of the aforementioned diseases. Mutants found to be sensitive to A-NO2- included PA0964 (pmpR, PQS biosynthesis), PA4455 (probable ABC transporter permease), katA (major catalase, KatA) and rhlR (quorum sensing regulator).
View Article and Find Full Text PDFThe pregnane X receptor (PXR) is a ligand-activated nuclear receptor that acts as a xenobiotic sensor, responding to compounds of foreign origin, including pharmaceutical compounds, environmental contaminants, and natural products, to induce transcriptional events that regulate drug detoxification and efflux pathways. As such, the PXR is thought to play a key role in protecting the host from xenobiotic exposure. More recently, the PXR has been reported to regulate the expression of innate immune receptors in the intestine and modulate inflammasome activation in the vasculature.
View Article and Find Full Text PDFThe NOD-like receptor (NLR) family of proteins is a group of pattern recognition receptors (PRRs) known to mediate the initial innate immune response to cellular injury and stress. The NLRP proteins represent a fourteen-member subset of the NLR family that contains an N-terminal pyrin domain. Some NLRs are known to form multi-protein complexes known as inflammasomes.
View Article and Find Full Text PDFBackground: Anti-glomerular basement membrane (anti-GBM) disease is characterized by circulating IgG glomerular basement membrane antibodies and is clinically expressed as a rapidly progressive crescentic glomerulonephritis (GN), with 30-60% of patients also developing pulmonary hemorrhage. Classically, the renal biopsy shows glomerular crescent formation, bright linear staining of glomerular basement membranes (GBM) for IgG on direct immunofluorescence (IF), and the serologic presence of circulating anti-GBM antibodies. Recently, patients with linear IgG IF staining, undetectable circulating anti-GBM antibodies and glomerular changes atypical for anti-GBM disease have been described as "atypical anti-GBM disease", with a distinctly more benign clinical course than typical anti-GBM disease.
View Article and Find Full Text PDFWe describe a case of biopsy-proven dabigatran related nephropathy in a patient without underlying IgA nephropathy. To date, dabigatran related nephropathy was only reported in patients with concurrent or undiagnosed IgA nephropathy, suggesting that it may predispose patients to dabigatran associated injury. The patient is an 81-year-old woman with multiple medical comorbidities, including nonvalvular atrial fibrillation, who was anticoagulated with dabigatran.
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