The C3-C3aR axis modulates trained immunity in alveolar macrophages.

Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity - enhanced secondary responses of innate immune cells after prior exposure - is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that , trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury.

Diurnal rhythms in varicella vaccine effectiveness.

BACKGROUNDImmune processes are influenced by circadian rhythms. We evaluate the association between varicella vaccine administration time of day and vaccine effectiveness.METHODSA national cohort, children younger than 6 years, were enrolled between January 2002 and December 2023.

Nanoparticle targeting of neutrophil glycolysis prevents lung ischemia-reperfusion injury.

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]).

Circadian rhythms in solid organ transplantation.

Circadian rhythms are daily cycles in physiology that can affect medical interventions. This review considers how these rhythms may relate to solid organ transplantation. It begins by summarizing the mechanism for circadian rhythm generation known as the molecular clock, and basic research connecting the clock to biological activities germane to organ acceptance.

Circadian immunity from bench to bedside: a practical guide.

The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions.

Multi-organ phenotypes in mice lacking latent TGFβ binding protein 2 (LTBP2).

Background: Latent TGFβ binding protein-2 (LTBP2) is a fibrillin 1 binding component of the microfibril. LTBP2 is the only LTBP protein that does not bind any isoforms of TGFβ, although it may interfere with the function of other LTBPs or interact with other signaling pathways.

Results: Here, we investigate mice lacking Ltbp2 (Ltbp2 ) and identify multiple phenotypes that impact bodyweight and fat mass, and affect bone and skin development.

Biological rhythms in COVID-19 vaccine effectiveness in an observational cohort study of 1.5 million patients.

BACKGROUNDCircadian rhythms are evident in basic immune processes, but it is unclear if rhythms exist in clinical endpoints like vaccine protection. Here, we examined associations between COVID-19 vaccination timing and effectiveness.METHODSWe retrospectively analyzed a large Israeli cohort with timestamped COVID-19 vaccinations (n = 1,515,754 patients over 12 years old, 99.

Perfect timing: circadian rhythms, sleep, and immunity - an NIH workshop summary.

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential.

Measuring Diurnal Rhythms in Autophagic and Proteasomal Flux.

Cells employ several methods for recycling unwanted proteins and other material, including lysosomal and non-lysosomal pathways. The main lysosome-dependent pathway is called autophagy, while the primary non-lysosomal method for protein catabolism is the ubiquitin-proteasome system. Recent studies in model organisms suggest that the activity of both autophagy and the ubiquitin-proteasome system is not constant across the day but instead varies according to a daily (circadian) rhythm.

Why Lungs Keep Time: Circadian Rhythms and Lung Immunity.

Circadian rhythms are daily cycles in biological function that are ubiquitous in nature. Understood as a means for organisms to anticipate daily environmental changes, circadian rhythms are also important for orchestrating complex biological processes such as immunity. Nowhere is this more evident than in the respiratory system, where circadian rhythms in inflammatory lung disease have been appreciated since ancient times.

Adventures in spacetime: circadian rhythms and the dynamics of protein catabolism.

Circadian rhythms help cells to organize complex processes, but how they shape the kinetics of protein catabolism is unclear. In a recent paper, we employed proteomics to map daily biological rhythms in autophagic flux in mouse liver, and correlated these rhythms with proteasome activity. We also explored the effect of inflammation caused by endotoxin on autophagy dynamics.

Diurnal Rhythms Spatially and Temporally Organize Autophagy.

Circadian rhythms are a hallmark of physiology, but how such daily rhythms organize cellular catabolism is poorly understood. Here, we used proteomics to map daily oscillations in autophagic flux in mouse liver and related these rhythms to proteasome activity. We also explored how systemic inflammation affects the temporal structure of autophagy.

Establishment of the early cilia preassembly protein complex during motile ciliogenesis.

Motile cilia are characterized by dynein motor units, which preassemble in the cytoplasm before trafficking into the cilia. Proteins required for dynein preassembly were discovered by finding human mutations that result in absent ciliary motors, but little is known about their expression, function, or interactions. By monitoring ciliogenesis in primary airway epithelial cells and MCIDAS-regulated induced pluripotent stem cells, we uncovered two phases of expression of preassembly proteins.

Long noncoding RNA FOXD3-AS1 regulates oxidative stress-induced apoptosis sponging microRNA-150.

The function of most human long noncoding RNAs (lncRNAs) remains unclear. Our studies identified a highly up-regulated mammalian lncRNA, , known as in mice, in the setting of hyperoxia/reactive oxygen species (ROS)-induced lung injury. We found that ROS induced a robust expression of FOXD3 in mouse lung tissue.

MiR-15a/16 Regulates Apoptosis of Lung Epithelial Cells after Oxidative Stress.

Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. Death receptor-associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood.

Sleep Loss and Circadian Rhythm Disruption in the Intensive Care Unit.

Critical illness is associated with profound sleep disruption. Causality is diverse and includes physiologic, psychological, and environmental factors. There are limited pharmacologic interventions available to treat sleep disturbances in critical illness; however, multidisciplinary strategies that alter the intensive care unit (ICU) environment and cluster care delivery have shown promise in sleep and circadian promotion and delirium reduction.

Circadian rhythm reprogramming during lung inflammation.

Circadian rhythms are known to regulate immune responses in healthy animals, but it is unclear whether they persist during acute illnesses where clock gene expression is disrupted by systemic inflammation. Here we use a genome-wide approach to investigate circadian gene and metabolite expression in the lungs of endotoxemic mice and find that novel cellular and molecular circadian rhythms are elicited in this setting. The endotoxin-specific circadian programme exhibits unique features, including a divergent group of rhythmic genes and metabolites compared with the basal state and a distinct periodicity and phase distribution.

Metabolomic derangements are associated with mortality in critically ill adult patients.

Objective: To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.

Rationale: Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible.

Methods: We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI).

Autophagic flux and oxidative capacity of skeletal muscles during acute starvation.

Autophagy is an important proteolytic pathway in skeletal muscles. The roles of muscle fiber type composition and oxidative capacity remain unknown in relation to autophagy. The diaphragm (DIA) is a fast-twitch muscle fiber with high oxidative capacity, the tibialis anterior (TA) muscle is a fast-twitch muscle fiber with low oxidative capacity, and the soleus muscle (SOL) is a slow-twitch muscle with high oxidative capacity.

Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-β receptor I internalization and inhibiting transforming growth factor-β1 signaling.

Rationale: Alveolar transforming growth factor (TGF)-β1 signaling and expression of TGF-β1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-β receptor TβRI inhibits TGF-β signaling and could attenuate development of experimental lung fibrosis.

Objectives: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-β1 signaling in alveolar epithelial cells.

The emerging importance of autophagy in pulmonary diseases.

Important cellular processes such as inflammation, apoptosis, differentiation, and proliferation confer critical roles in the pathogenesis of human diseases. In the past decade, an emerging process named "autophagy" has generated intense interest in both biomedical research and clinical medicine. Autophagy is a regulated cellular pathway for the turnover of organelles and proteins by lysosomal-dependent processing.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding.

Autophagy in idiopathic pulmonary fibrosis.

Background: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis.

Inflammasome-regulated cytokines are critical mediators of acute lung injury.

Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g.