Background
Epithelial and endothelial barrier integrity, essential for homeostasis, is maintained by cellular boarder structures known as tight junctions (TJs). In critical illness, TJs may become ...disrupted, resulting in barrier dysfunction manifesting as capillary leak, pulmonary edema, gut bacterial translocation, and multiple organ failure. We aim to provide a clinically focused overview of TJ structure and function and systematically review and analyze all studies assessing markers of endothelial and epithelial TJ breakdown correlated with clinical outcomes in critically ill humans.
Methods
We systematically searched MEDLINE, EMBASE, and PubMed. Additional articles were identified by targeted searches. We included studies that looked at the relationship between biomarkers of endothelial or epithelial TJ structure or function and critical illness. Results were qualitatively analyzed due to sample size and heterogeneity.
Results
A total of 5297 abstracts met search criteria, of which 150 articles met requirements for full text review. Of these, 30 studies met inclusion criteria. Fifteen of the 30 reports investigated proteins of endothelial tight junctions and 15 investigated epithelial TJ markers, exclusively in the gastrointestinal epithelium. No studies investigated TJ-derived proteins in primary cardiac or pulmonary pathology.
Conclusions
TJ integrity is essential for homeostasis. We identified multiple studies that indicate TJs are disrupted by critical illness. These studies highlight the significance of barrier disruption across many critical disease states and correlate TJ-associated markers to clinically relevant outcomes. Further study on the role of multiple tissue-specific claudins, particularly in the setting of respiratory or cardiac failure, may lead to diagnostic and therapeutic advances.
Systematic review registration
This systematic review is registered in the PROSPERO database:
CRD42017074546
.
Improving the performance of nanocarriers remains a major challenge in the clinical translation of nanomedicine. Efforts to optimize nanoparticle formulations typically rely on tuning the surface ...density and thickness of stealthy polymer coatings, such as poly(ethylene glycol) (PEG). Here, we show that modulating the surface topography of PEGylated nanoparticles using bottlebrush block copolymers (BBCPs) significantly enhances circulation and tumor accumulation, providing an alternative strategy to improve nanoparticle coatings. Specifically, nanoparticles with rough surface topography achieve high tumor cell uptake in vivo due to superior tumor extravasation and distribution compared to conventional smooth-surfaced nanoparticles based on linear block copolymers. Furthermore, surface topography profoundly impacts the interaction with serum proteins, resulting in the adsorption of fundamentally different proteins onto the surface of rough-surfaced nanoparticles formed from BBCPs. We envision that controlling the nanoparticle surface topography of PEGylated nanoparticles will enable the design of improved nanocarriers in various biomedical applications.
Capillary endothelial cells (ECs) maintain a semi‐permeable barrier between the blood and tissue by forming inter‐EC tight junctions (TJs), regulating selective transport of fluid and solutes. ...Overwhelming inflammation, as occurs in sepsis, disrupts these TJs, leading to leakage of fluid, proteins, and small molecules into the tissues. Mechanistically, disruption of capillary barrier function is mediated by small Rho‐GTPases, such as RhoA, ‐B, and ‐C, which are activated by guanine nucleotide exchange factors (GEFs) and disrupted by GTPase‐activating factors (GAPs). We previously reported that a mutation in a specific RhoB GAP (p190BRhoGAP) underlays a hereditary capillary leak syndrome. Tumor necrosis factor (TNF) treatment disrupts TJs in cultured human microvascular ECs, a model of capillary leak. This response requires new gene transcription and involves increased RhoB activation. However, the specific GEF that activates RhoB in capillary ECs remains unknown. Transcriptional profiling of cultured tight junction‐forming human dermal microvascular endothelial cells (HDMECs) revealed that 17 GEFs were significantly induced by TNF. The function of each candidate GEF was assessed by short interfering RNA depletion and trans‐endothelial electrical resistance screening. Knockown of ArhGEF10 reduced the TNF‐induced loss of barrier which was phenocopied by RhoB or dual ArhGEF10/RhoB knockdown. ArhGEF10 knockdown also reduced the extent of TNF‐induced RhoB activation and disruption at tight junctions. In a cell‐free assay, immunoisolated ArhGEF10 selectively catalyzed nucleotide exchange to activate RhoB, but not RhoA or RhoC. We conclude ArhGEF10 is a TNF‐induced RhoB‐selective GEF that mediates TJ disruption and barrier loss in human capillary endothelial cells.
Summertime Arctic aerosol size distributions are strongly controlled by natural regional emissions. Within this context, we use a chemical transport model with size-resolved aerosol microphysics ...(GEOS-Chem-TOMAS) to interpret measurements of aerosol size distributions from the Canadian Arctic Archipelago during the summer of 2016, as part of the "NETwork on Climate and Aerosols: Addressing key uncertainties in Remote Canadian Environments" (NETCARE) project. Our simulations suggest that condensation of secondary organic aerosol (SOA) from precursor vapors emitted in the Arctic and near Arctic marine (ice-free seawater) regions plays a key role in particle growth events that shape the aerosol size distributions observed at Alert (82.5.sup.â N, 62.3.sup.â W), Eureka (80.1.sup.â N, 86.4.sup.â W), and along a NETCARE ship track within the Archipelago. We refer to this SOA as Arctic marine SOA (AMSOA) to reflect the Arctic marine-based and likely biogenic sources for the precursors of the condensing organic vapors.
Overwhelming inflammation in the setting of acute critical illness induces capillary leak resulting in hypovolemia, edema, tissue dysoxia, organ failure and even death. The tight junction ...(TJ)‐dependent capillary barrier is regulated by small GTPases, but the specific regulatory molecules most active in this vascular segment under such circumstances are not well described. We set out to identify GTPase regulatory molecules specific to endothelial cells (EC) that form TJs. Transcriptional profiling of confluent monolayers of TJ‐forming human dermal microvascular ECs (HDMECs) and adherens junction only forming‐human umbilical vein EC (HUVECs) demonstrate ARHGEF12 is basally expressed at higher levels and is only downregulated in HDMECs by junction‐disrupting tumor necrosis factor (TNF). HDMECs depleted of ArhGEF12 by siRNA demonstrate a significantly exacerbated TNF‐induced decrease in trans‐endothelial electrical resistance and disruption of TJ continuous staining. ArhGEF12 is established as a RhoA‐GEF in HUVECs and its knock down would be expected to reduce RhoA activity and barrier disruption. Pulldown of active GEFs from HDMECs depleted of ArhGEF12 and treated with TNF show decreased GTP‐bound Rap1A after four hours but increased GTP‐bound RhoA after 12 h. In cell‐free assays, ArhGEF12 immunoprecipitated from HDMECs is able to activate both Rap1A and RhoA, but not act on Rap2A‐C, RhoB‐C, or even Rap1B which shares 95% sequence identity with Rap1A. We conclude that in TJ‐forming HDMECs, ArhGEF12 selectively activates Rap1A to limit capillary barrier disruption in a mechanism independent of cAMP‐mediated Epac1 activation.
A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multistep process that involves sequential cell-cell interactions of circulating leukocytes with IL-1- or ...TNF-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a proinflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, although neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA sequencing analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and they also stimulate neutrophil production of proinflammatory molecules, including TNF, IL-1α, IL-1β, and IL-8. Furthermore, IL-17-activated PCs, but not ECs, can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondrial outer membrane permeabilization and caspase-9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by conditioned media from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space.
We describe a fatal case of pediatric systemic capillary leak (Clarkson's disease) associated with a point mutation in p190BRhoGAP. Dermal microvascular endothelial cells (ECs) isolated from this ...patient form monolayers with similar levels and distribution of junctional proteins and transendothelial electrical resistance compared with normal human dermal microvascular ECs. However, patient-derived ECs demonstrate a greater increase in permeability and impaired recovery of barrier function in response to tumor necrosis factor (TNF) compared with normal donor EC cultures. TNF transiently activates RhoB in ECs coincident with developing leak, and inactivation of RhoB correlates with barrier recovery. The mutation in p190BRhoGAP impairs RhoB inactivation, and the mutant phenotype of patient-derived ECs is replicated by siRNA knockdown of p190BRhoGAP in normal ECs. These data suggest a previously unknown function for p190BRhoGAP in control of capillary EC barrier function that may also be important in acquired systemic capillary leak associated with critical illness in humans.
Resolution of impaired microvascular flow may lag the normalization of macrocirculatory variables. The significance of microcirculatory dysfunction in critically ill children and neonates is unknown, ...but microcirculatory variables can be measured using Doppler or videomicroscopy imaging techniques. We outline the current understanding of the role of the microcirculation in critical illness, review methods for its assessment, and perform a systematic review of how it has been monitored in critically ill neonates and children.
Systematic review (PROSPERO CRD42019117993).
Not applicable.
Not applicable.
None.
We systematically searched MEDLINE, EMBASE, PubMed, and Web of Science. We included studies of critically ill patients 0 to 18 years old investigating microcirculatory blood flow. Two reviewers analyzed abstracts and articles. Results were qualitatively analyzed due to study heterogeneity. A total of 2,559 abstracts met search criteria, of which 94 underwent full-text review. Of those, 36 met inclusion criteria. Seven studies investigated microcirculatory changes in critically ill children. Twenty studies investigated the microcirculatory changes in neonates with variable diagnoses compared with a diverse set of clinical endpoints. Nine studies assessed the effects of age, sex, and birth weight on microvascular flow in neonates. Across all studies, microcirculatory dysfunction was associated with poor outcomes and may not correlate with observed macrovascular function.
Assessment of microvascular flow in critically ill children and neonates is possible, although significant challenges remain. In many such patients, microvascular blood flow is disrupted despite medical management targeting normalized macrovascular variables. Future studies are needed to define normal pediatric microvascular flow variables and to assess the impact of patient and treatment factors on its function.
Abstract
Phyllachora maydis
is a fungal pathogen causing tar spot of corn (
Zea mays
L.), a new and emerging, yield-limiting disease in the United States. Since being first reported in Illinois and ...Indiana in 2015,
P. maydis
can now be found across much of the corn growing regions of the United States. Knowledge of the epidemiology of
P. maydis
is limited but could be useful in developing tar spot prediction tools. The research presented here aims to elucidate the environmental conditions necessary for the development of tar spot in the field and the creation of predictive models to anticipate future tar spot epidemics. Extended periods (30-day windowpanes) of moderate mean ambient temperature (18–23 °C) were most significant for explaining the development of tar spot. Shorter periods (14- to 21-day windowpanes) of moisture (relative humidity, dew point, number of hours with predicted leaf wetness) were negatively correlated with tar spot development. These weather variables were used to develop multiple logistic regression models, an ensembled model, and two machine learning models for the prediction of tar spot development. This work has improved the understanding of
P. maydis
epidemiology and provided the foundation for the development of a predictive tool for anticipating future tar spot epidemics.
Measurements of ocean surface and atmospheric dimethyl sulfide (DMS) and particle size distributions were made in the Canadian Arctic Archipelago during the fall of 2007 and the late summer of 2008 ...aboard the Canadian Coast Guard Ship Amundsen. Nucleation‐mode particles were observed during the 2008 cruise, which took place in the eastern Arctic from August to September when the atmosphere and ocean were more photo‐active as compared to the October 2007 transit in the Beaufort Sea during which no nucleation/growth events were observed. The observed nucleation periods in 2008 coincided with high atmospheric and ocean surface DMS concentrations, suggesting that the particles originated from marine biogenic sources. An aerosol microphysics box model was used to simulate nucleation given the measured conditions in the marine boundary layer. Although other sources may have contributed, we find that the newly formed particles can be accounted for by a marine biogenic DMS source for combinations of the following parameters: OH ≥ 3 × 105 molecules cm−3, DMS mixing ratio is ≥ 100 pptv, the activation coefficient is ≤ 10−7 and the background particle concentration is ≤ 100 cm−3.
Key Points
Particle nucleation was observed in the Canadian Arctic
These events coincided with high DMS levels in the atmosphere and ocean
Model results suggest that DMS oxidation products could have caused nucleation
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