Access provided by Elsevier BV Bibliographic DatabasesOcialPublicationsof theAmericanThoracicSociety AJRCCM AJRCMB AnnalsATS ATS Scholar ATSAmerican Journal of Respiratory Cell andMolecular ...BiologyHome American Journal of Respiratory Celland Molecular Biology List of Issues Volume 70 Issue 3Article Tools S1PR2 A Fulcrum in the Balance of Type 1 and Type 2 Responsesduring Sepsisinduced Acute Lung InjuryPhilip A. Verhoef Author Aliationshttpsdoi.org10.1165rcmb.20230433ED PubMed 38226863CommentsThis article is open access and distributed under the terms of the Creative CommonsAttribution NonCommercial No Derivatives License 4.0. For commercial usage and reprintsplease email Diane Gern.First Page Full Text References Supplements PDF RelatedThe paradigm of type 1 and type 2 immune responses was rst described nearly 40years agowith the discovery of Thelper type 1 Th1 cells secreting inammatory cytokines such as IFNin response to bacterial and viral infection and Th2 cells releasing IL4 in the context ofextracellular parasite and helminth infection 1 2. Since then numerous other cells andcytokines have been incorporated into an increasingly complex model with additionalresponses identied e.g. Th17associated type 3 responses as well as newly discoveredfunctions e.g. the role of type 2 responses in tissue repair and homeostasis 3. Whatremains clear however is the notion of equilibrium Type 1 responses and type 2 responsescounterbalance each other and a perturbation of this balance is often associated with thedevelopment of disease 3.It is through this lens that Gong and colleagues pp. 215225 approached their study ofsepsisinduced acute lung injury ALI in this issue of the Journal 4. Sepsis is the mostcommon cause of acute respiratory distress syndrome ARDS with over 200000 patientsyridentied with sepsisinduced ARDS in the United States alone 5. Sepsisinduced ALI occurswhen an infection either within the lungs or extrapulmonary triggers a systemicinammatory type 1 or type 3 response resulting in damage to the alveolarcapillary barrierand the canonical development of pulmonary edema and impaired oxygenation. Consistentwith the aforementioned equilibrium hypothesis a growing body of evidence suggests that135PDFHelptype 2
A committed precursor to innate lymphoid cells Constantinides, Michael G; McDonald, Benjamin D; Verhoef, Philip A ...
Nature (London),
04/2014, Letnik:
508, Številka:
7496
Journal Article
Recenzirano
Odprti dostop
Innate lymphoid cells (ILCs) specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair at mucosal barriers. Their diversity and ...similarities with previously characterized natural killer (NK) cells and lymphoid tissue inducers (LTi) have prompted a provisional classification of all innate lymphocytes into groups 1, 2 and 3 solely on the basis of cytokine properties, but their developmental pathways and lineage relationships remain elusive. Here we identify and characterize a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor previously associated with NK T cell development, by using lineage tracing and transfer studies. PLZF(high) cells were committed ILC progenitors with multiple ILC1, ILC2 and ILC3 potential at the clonal level. They excluded classical LTi and NK cells, but included a peculiar subset of NK1.1(+)DX5(-) 'NK-like' cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZF(high) precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages. These findings establish novel lineage relationships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defining role of PLZF in the differentiation of innate lymphocytes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The only known study evaluating SARS development in hospital workers was a retrospective study conducted prior to the widespread use of HFNC showing that development of SARS occurred in tracheal ...intubation (35%), HFNC 8%, and 38% (NIPPV) 3; this suggests that both non-invasive (including HFNC) and invasive ventilation approaches carry significant risk. ...since the data regarding transmission are unclear, we suggest, in addition to a negative pressure room, reverse isolation protection efforts with patients on HFNC wearing a mask over the nasal interface or a contained respiratory hood. 1. Comparison of high-flow nasal cannula versus oxygen face mask for environmental bacterial contamination in critically ill pneumonia patients: a randomized controlled crossover trial.
Among the variety of tissue-resident NK-like populations recently distinguished from recirculating classical NK (cNK) cells, liver innate lymphoid cells (ILC) type 1 (ILC1s) have been shown to ...represent a distinct lineage that originates from a novel promyelocytic leukaemia zinc finger (PLZF)-expressing ILC precursor (ILCP) strictly committed to the ILC1, ILC2, and ILC3 lineages. Here, using PLZF-reporter mice and cell transfer assays, we studied the developmental progression of ILC1s and demonstrated substantial overlap with stages previously ascribed to the cNK lineage, including pre–pro-NK, pre-NK precursor (pre-NKP), refined NKP (rNKP), and immature NK (iNK). Although they originated from different precursors, the ILC1 and cNK lineages followed a parallel progression at early stages and diverged later at the iNK stage, with a striking predominance of ILC1s over cNKs early in ontogeny. Although a limited set of ILC1 genes depended on PLZF for expression, characteristically includingIl7r,most of these genes were also differentially expressed between ILC1s and cNKs, indicating that PLZF together with other, yet to be defined, factors contribute to the divergence between these lineages.
Sepsis is a heterogeneous syndrome, and identifying clinically relevant subphenotypes is essential.
To identify novel subphenotypes in hospitalized patients with infection using longitudinal ...temperature trajectories.
In the model development cohort, inpatient admissions meeting criteria for infection in the emergency department and receiving antibiotics within 24 hours of presentation were included. Temperature measurements within the first 72 hours were compared between survivors and nonsurvivors. Group-based trajectory modeling was performed to identify temperature trajectory groups, and patient characteristics and outcomes were compared between the groups. The model was then externally validated at a second hospital using the same inclusion criteria.
A total of 12,413 admissions were included in the development cohort, and 19,053 were included in the validation cohort. In the development cohort, four temperature trajectory groups were identified: "hyperthermic, slow resolvers" (
= 1,855; 14.9% of the cohort); "hyperthermic, fast resolvers" (
= 2,877; 23.2%); "normothermic" (
= 4,067; 32.8%); and "hypothermic" (
= 3,614; 29.1%). The hypothermic subjects were the oldest and had the most comorbidities, the lowest levels of inflammatory markers, and the highest in-hospital mortality rate (9.5%). The hyperthermic, slow resolvers were the youngest and had the fewest comorbidities, the highest levels of inflammatory markers, and a mortality rate of 5.1%. The hyperthermic, fast resolvers had the lowest mortality rate (2.9%). Similar trajectory groups, patient characteristics, and outcomes were found in the validation cohort.
We identified and validated four novel subphenotypes of patients with infection, with significant variability in inflammatory markers and outcomes.
Purpose
Sepsis is a heterogeneous syndrome and identification of sub-phenotypes is essential. This study used trajectories of vital signs to develop and validate sub-phenotypes and investigated the ...interaction of sub-phenotypes with treatment using randomized controlled trial data.
Methods
All patients with suspected infection admitted to four academic hospitals in Emory Healthcare between 2014–2017 (training cohort) and 2018–2019 (validation cohort) were included. Group-based trajectory modeling was applied to vital signs from the first 8 h of hospitalization to develop and validate vitals trajectory sub-phenotypes. The associations between sub-phenotypes and outcomes were evaluated in patients with sepsis. The interaction between sub-phenotype and treatment with balanced crystalloids versus saline was tested in a secondary analysis of SMART (Isotonic Solutions and Major Adverse Renal Events Trial).
Results
There were 12,473 patients with suspected infection in training and 8256 patients in validation cohorts, and 4 vitals trajectory sub-phenotypes were found. Group A (
N
= 3483, 28%) were hyperthermic, tachycardic, tachypneic, and hypotensive. Group B (
N
= 1578, 13%) were hyperthermic, tachycardic, tachypneic (not as pronounced as Group A) and hypertensive. Groups C (
N
= 4044, 32%) and D (
N
= 3368, 27%) had lower temperatures, heart rates, and respiratory rates, with Group C normotensive and Group D hypotensive. In the 6,919 patients with sepsis, Groups A and B were younger while Groups C and D were older. Group A had the lowest prevalence of congestive heart failure, hypertension, diabetes mellitus, and chronic kidney disease, while Group B had the highest prevalence. Groups A and D had the highest vasopressor use (
p
< 0.001 for all analyses above). In logistic regression, 30-day mortality was significantly higher in Groups A and D (
p
< 0.001 and
p
= 0.03, respectively). In the SMART trial, sub-phenotype significantly modified treatment effect (
p
= 0.03). Group D had significantly lower odds of mortality with balanced crystalloids compared to saline (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.23–0.67,
p
< 0.001).
Conclusion
Sepsis sub-phenotypes based on vital sign trajectory were consistent across cohorts, had distinct outcomes, and different responses to treatment with balanced crystalloids versus saline.
This study evaluates the performance of temporal thermometry compared with oral thermometry in detecting fever in Black and White patients hospitalized with infection.
Background The transcription factor promyelocytic leukemia zinc finger (PLZF) is transiently expressed during development of type 2 innate lymphoid cells (ILC2s) but is not present at the mature ...stage. We hypothesized that PLZF-deficient ILC2s have functional defects in the innate allergic response and represent a tool for studying innate immunity in a mouse with a functional adaptive immune response. Objective We determined the consequences of PLZF deficiency on ILC2 function in response to innate and adaptive immune stimuli by using PLZF−/− mice and mixed wild-type:PLZF−/− bone marrow chimeras. Methods PLZF−/− mice, wild-type littermates, or mixed bone marrow chimeras were treated with the protease allergen papain or the cytokines IL-25 and IL-33 or infected with the helminth Nippostrongylus brasiliensis to induce innate type 2 allergic responses. Mice were sensitized with intraperitoneal ovalbumin-alum, followed by intranasal challenge with ovalbumin alone, to induce adaptive TH 2 responses. Lungs were analyzed for immune cell subsets, and alveolar lavage fluid was analyzed for ILC2-derived cytokines. In addition, ILC2s were stimulated ex vivo for their capacity to release type 2 cytokines. Results PLZF-deficient lung ILC2s exhibit a cell-intrinsic defect in the secretion of IL-5 and IL-13 in response to innate stimuli, resulting in defective recruitment of eosinophils and goblet cell hyperplasia. In contrast, the adaptive allergic inflammatory response to ovalbumin and alum was unimpaired. Conclusions PLZF expression at the innate lymphoid cell precursor stage has a long-range effect on the functional properties of mature ILC2s and highlights the importance of these cells for innate allergic responses in otherwise immunocompetent mice.
Quantification of pathogen and host biomarkers is essential for the diagnosis, monitoring, and treatment of infectious diseases. Here, we demonstrate sensitive and rapid quantification of bacterial ...load and cytokines from human biological samples to generate actionable hypotheses. Our digital assay measures IL-6 and TNF-α proteins, gram-negative (GN) and gram-positive (GP) bacterial DNA, and the antibiotic-resistance gene bla
with femtomolar sensitivity. We use our method to characterize bronchoalveolar lavage fluid from patients with asthma, and find elevated GN bacteria and IL-6 levels compared to healthy subjects. We then analyze plasma from patients with septic shock and find that increasing levels of IL-6 and bla
are associated with mortality, while decreasing IL-6 levels are associated with recovery. Surprisingly, lower GN bacteria levels are associated with higher probability of death. Applying decision-tree analysis to our measurements, we are able to predict mortality and rate of recovery from septic shock with over 90% accuracy.
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