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The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.
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BACKGROUND: Dystrophic epidermolysis bullosa (DEB) describes a rare genetic blistering disorder characterized by fragile skin. This study aimed to classify the frequency, demographics, cost, and comorbidities associated with emergency department (ED) visits due to DEB. METHODS: The Nationwide Emergency Department Sample (NEDS) was analyzed for pediatric (age <18) ED visits from 2015 to 2019. DEB was identified with ICD-10-CM code Q81.2. Weighted frequency, prevalence, and 95% confidence intervals (CIs) of comorbidities were determined among ED visits with and without a DEB diagnosis. RESULTS: From 2015 to 2019, 53 (weighted 242) cases of DEB among 27,223,220 pediatric ED visits were captured. Patients with DEB were more likely to visit the ED in summer compared with those without a diagnosis of DEB (35.7% vs. 21.4%, P < .05). More than half of patients with DEB were admitted to the hospital (56.2%, 95% CI: 39.3-72.5, P < .001) versus only 3.4% (95% CI: 3.1-3.7) of other patients. For ED visits with a secondary DEB diagnosis, the top three primary diagnoses were fever, constipation, and bone marrow transplant aftercare. Patients with DEB had higher rates of hypertension, cellulitis, sepsis, acute and chronic kidney injury, esophageal obstruction, gastroesophageal reflux disease, cardiomyopathy, and anxiety, compared to patients without DEB (all P < .001). CONCLUSIONS: DEB is a complex blistering disorder with multisystemic manifestations. Patients with DEB have significantly higher admission rates and commonly present with infectious or gastrointestinal complications. Understanding the features of ED visits due to DEB can better prepare healthcare teams and improve patient outcomes.
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Cutaneous T-cell lymphomas (CTCL) are a rare group of T-cell neoplasms which infiltrate the skin and can result in substantial morbidity and mortality. Risk factors for CTCL are still poorly understood though recent studies suggest chemical exposures may play a role in its development. To further characterize patient-centered risk factors for CTCL, especially compared with matched controls, we performed one of the largest prospective cohort survey studies to date to examine patient-reported exposures and health-related quality of life (HRQoL) in association with concurrent clinical disease characteristics. Patient demographics, lifestyle factors, and chemical exposures were collected via clinical data and surveys. Descriptive statistics, ANOVA, Chi-square tests and t tests were utilized to compare patient-reported exposures and HRQoL in patients with CTCL versus matched healthy controls (HC). Statistically significant differences were identified between patients and HC in terms of race (non-white race 22.4% in CTCL patients vs. 18.8% in HC, P = 0.01), and education level (high school or less 41.6% in CTCL patients vs. 14.3% in HC, P = 0.001), but not with Fitzpatrick skin type (P = 0.11) or smoking status (P = 0.28). Notably, 36.0% of the CTCL patients reported exposures to chemicals, a near threefold increased percentage when compared to HC (12.9%). Among various chemical exposures, 27.0% of the CTCL patients specifically reported industrial chemical exposure, a more than two-fold increased percentage when compared to HC (12.9%). Itch and pain were significantly associated with skin disease severity (as evaluated by CTCL-specific mSWAT score) in advanced stage disease (stages IIB-IVB) (r = 0.48 and 0.57, P < 0.05). Itch and body mass index (BMI) were weakly associated with skin disease severity in early-stage disease (stages IA-IIA) (r = 0.27 and 0.20, P < 0.05).
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Linfoma Cutáneo de Células T , Médicos , Neoplasias Cutáneas , Humanos , Estudios de Cohortes , Estudios Prospectivos , Calidad de Vida , Linfoma Cutáneo de Células T/epidemiología , Prurito , Neoplasias Cutáneas/epidemiologíaRESUMEN
PBRM1 is frequently mutated in cancers of epithelial origin. How PBRM1 regulates normal epithelial homeostasis, prior to cancer initiation, remains unclear. Here, we show that PBRM1's gene regulatory roles differ drastically between cell states, leveraging human skin epithelium (epidermis) as a research platform. In progenitors, PBRM1 predominantly functions to repress terminal differentiation to sustain progenitors' regenerative potential; in the differentiation state, however, PBRM1 switches toward an activator. Between these two cell states, PBRM1 retains its genomic binding but associates with differential interacting proteins. Our targeted screen identified the E3 SUMO ligase PIAS1 as a key interactor. PIAS1 co-localizes with PBRM1 on chromatin to directly repress differentiation genes in progenitors, and PIAS1's chromatin binding drastically diminishes in differentiation. Furthermore, SUMOylation contributes to PBRM1's repressive function in progenitor maintenance. Thus, our findings highlight PBRM1's cell-state-specific regulatory roles influenced by its protein interactome despite its stable chromatin binding.
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Multiómica , Ubiquitina-Proteína Ligasas , Humanos , Ubiquitina-Proteína Ligasas/genética , Regulación de la Expresión Génica , Sumoilación , Cromatina/genética , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Proteínas Inhibidoras de STAT Activados/genéticaRESUMEN
Melanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1), controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in the surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressor Slug, and consequently decreases expression of the Dsg1 transcriptional activator Grhl1. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.
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Desmogleína 1 , Queratinocitos , Melanoma , Humanos , Movimiento Celular , Desmogleína 1/genética , Epidermis , Melanoma/genética , Melanoma/patología , Microambiente Tumoral/genéticaRESUMEN
Keloids are benign, fibroproliferative dermal tumors that typically form owing to abnormal wound healing. The current standard of care is generally ineffective and does not prevent recurrence. To characterize keloid scars and better understand the mechanism of their formation, we performed transcriptomic profiling of keloid biopsies from a total of 25 subjects of diverse racial and ethnic origins, 15 of whom provided a paired nonlesional sample, a longitudinal sample, or both. The transcriptomic signature of nonlesional skin biopsies from subjects with keloids resembled that of control skin at baseline but shifted to closely match that of keloid skin after dermal trauma. Peripheral keloid skin and rebiopsied surrounding normal skin both showed upregulation of epithelial-mesenchymal transition markers, extracellular matrix organization, and collagen genes. These keloid signatures strongly overlapped those from healthy wound healing studies, usually with greater perturbations, reinforcing our understanding of keloids as dysregulated and exuberant wound healing. In addition, 219 genes uniquely regulated in keloids but not in normal injured or uninjured skin were also identified. This study provides insights into mature and developing keloid signatures that can act as a basis for further validation and target identification in the search for transformative keloid treatments.
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Darier, Hailey-Hailey, and Grover diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. To better understand the underlying mechanisms leading to disease in these conditions, we performed RNA-seq on lesional skin samples from patients. The transcriptomic profiles of Darier, Hailey-Hailey, and Grover diseases were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases. Analysis of enriched pathways showed a shared increase in keratinocyte differentiation, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grover diseases. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in the acantholytic skin diseases. Furthermore, upstream regulator analysis suggested that a decrease in SRF/MRTF activity was responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared with normal skin. These findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grover diseases, and identify decreases in actin organization pathways as a unique signature present in these conditions.
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Actinas , Enfermedades de la Piel , Humanos , Piel/patología , Acantólisis/genética , Acantólisis/metabolismo , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/patologíaRESUMEN
Self-renewing somatic tissues rely on progenitors to support the continuous tissue regeneration. The gene regulatory network maintaining progenitor function remains incompletely understood. Here we show that NUP98 and RAE1 are highly expressed in epidermal progenitors, forming a separate complex in the nucleoplasm. Reduction of NUP98 or RAE1 abolishes progenitors' regenerative capacity, inhibiting proliferation and inducing premature terminal differentiation. Mechanistically, NUP98 binds on chromatin near the transcription start sites of key epigenetic regulators (such as DNMT1, UHRF1 and EZH2) and sustains their expression in progenitors. NUP98's chromatin binding sites are co-occupied by HDAC1. HDAC inhibition diminishes NUP98's chromatin binding and dysregulates NUP98 and RAE1's target gene expression. Interestingly, HDAC inhibition further induces NUP98 and RAE1 to localize interdependently to the nucleolus. These findings identified a pathway in progenitor maintenance, where HDAC activity directs the high levels of NUP98 and RAE1 to directly control key epigenetic regulators, escaping from nucleolar aggregation.
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Cromatina , Proteínas de Transporte Nucleocitoplasmático , Proteínas de Transporte Nucleocitoplasmático/química , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Cromatina/genética , Proteínas Asociadas a Matriz Nuclear/química , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas Asociadas a Matriz Nuclear/metabolismo , Sitios de UniónRESUMEN
BACKGROUND/OBJECTIVES: Healthcare transition (HCT) refers to movement from pediatric to adult healthcare models. Lack of HCT preparation contributes to poor health outcomes. This study measures readiness to transition in individuals with genetic skin conditions. METHODS: Participants signed IRB-approved consents/assents. Participants ages 14-22 years with genetic skin disorders were surveyed with measures of QoL (Children's Dermatology Life Quality Index/CDLQI or DLQI) and HCT readiness using the Transition Readiness Assessment Questionnaire (TRAQ) and adapted non-validated measures of Skin Knowledge and Psychosocial Factors (5 = highest readiness). Mean TRAQ was compared with historical data on controls and other chronic conditions (t-tests) and correlated (Pearson) with Skin Knowledge and Psychosocial. Multivariable regression compared demographics and QoL with transition readiness. RESULTS: A total of 45 participants were enrolled (mean age 17.8 years, 67% female, 71% White; disorders of cornification [n = 31], ectodermal dysplasias [n = 7], epidermolysis bullosa [n = 4], tuberous sclerosis [n = 3]). Mean TRAQ (3.3 ± 0.9) was lower than controls (3.9; p < .001) and some chronic disorders (sickle cell [3.7; p < .05], type 1 diabetes [3.7; p < .01]), but higher than with spina bifida (2.8; p < .001) and congenital heart disease (2.9; p < .01). Mean Skin Knowledge was 4.2 ± 1.0, and mean Psychosocial was 3.4 ± 0.8. TRAQ correlated strongly with Skin Knowledge (r = .61; p < .05), but not Psychosocial (r = .12; p = .6). Ages 14-17 years versus 18-22 years and public versus private insurance predicted lower TRAQ scores. Poor DLQI predicted higher TRAQ and Skin Knowledge, but poor DLQI and CDLQI predicted lower Psychosocial. CONCLUSIONS: Adolescents and young adults with genetic skin disorders demonstrated low transition readiness, especially among younger-aged and lower socioeconomic groups. We recommend a HCT intervention to improve health outcomes.
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Enfermedades de la Piel , Transición a la Atención de Adultos , Humanos , Adolescente , Femenino , Adulto Joven , Niño , Anciano , Masculino , Calidad de Vida , Encuestas y Cuestionarios , Enfermedades de la Piel/terapia , Enfermedad CrónicaRESUMEN
Melanoma arises from transformation of melanocytes in the basal layer of the epidermis where they are surrounded by keratinocytes, with which they interact through cell contact and paracrine communication. Considerable effort has been devoted to determining how the accumulation of oncogene and tumor suppressor gene mutations in melanocytes drive melanoma development. However, the extent to which alterations in keratinocytes that occur in the developing tumor niche serve as extrinsic drivers of melanoma initiation and progression is poorly understood. We recently identified the keratinocyte-specific cadherin, desmoglein 1 (Dsg1), as an important mediator of keratinocyte:melanoma cell crosstalk, demonstrating that its chronic loss, which can occur through melanoma cell-dependent paracrine signaling, promotes behaviors that mimic a malignant phenotype. Here we address the extent to which Dsg1 loss affects early steps in melanomagenesis. RNA-Seq analysis revealed that paracrine signals from Dsg1-deficient keratinocytes mediate a transcriptional switch from a differentiated to undifferentiated cell state in melanocytes expressing BRAFV600E, a driver mutation commonly present in both melanoma and benign nevi and reported to cause growth arrest and oncogene-induced senescence (OIS). Of ~220 differentially expressed genes in BRAFV600E cells treated with Dsg1-deficient conditioned media (CM), the laminin superfamily member NTN4/Netrin-4, which inhibits senescence in endothelial cells, stood out. Indeed, while BRAFV600E melanocytes treated with Dsg1-deficient CM showed signs of senescence bypass as assessed by increased senescence-associated ß-galactosidase activity and decreased p16, knockdown of NTN4 reversed these effects. These results suggest that Dsg1 loss in keratinocytes provides an extrinsic signal to push melanocytes towards oncogenic transformation once an initial mutation has been introduced.
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Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here - using a mouse model of hypercapnia exposure, cell lineage tracing, spatial transcriptomics, and 3D cultures - we show that hypercapnia limits ß-catenin signaling in alveolar type II (AT2) cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+ fibroblasts from those maintaining AT2 progenitor activity toward those that antagonize ß-catenin signaling, thereby limiting progenitor function. Constitutive activation of ß-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in patients with hypercapnia may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier and increasing lung flooding, ventilator dependency, and mortality.
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Hipercapnia , Vía de Señalización Wnt , Ratones , beta Catenina/metabolismo , Proliferación Celular , COVID-19/complicaciones , Hipercapnia/metabolismo , AnimalesRESUMEN
Pathogen clearance and resolution of inflammation in patients with pneumonia require an effective local T cell response. Nevertheless, local T cell activation may drive lung injury, particularly during prolonged episodes of respiratory failure characteristic of severe SARS-CoV-2 pneumonia. While T cell responses in the peripheral blood are well described, the evolution of T cell phenotypes and molecular signatures in the distal lung of patients with severe pneumonia caused by SARS-CoV-2 or other pathogens is understudied. Accordingly, we serially obtained 432 bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia and respiratory failure, including 74 unvaccinated patients with COVID-19, and performed flow cytometry, transcriptional, and T cell receptor profiling on sorted CD8+ and CD4+ T cell subsets. In patients with COVID-19 but not pneumonia secondary to other pathogens, we found that early and persistent enrichment in CD8+ and CD4+ T cell subsets correlated with survival to hospital discharge. Activation of interferon signaling pathways early after intubation for COVID-19 was associated with favorable outcomes, while activation of NF-κB-driven programs late in disease was associated with poor outcomes. Patients with SARS-CoV-2 pneumonia whose alveolar T cells preferentially targeted the Spike and Nucleocapsid proteins tended to experience more favorable outcomes than patients whose T cells predominantly targeted the ORF1ab polyprotein complex. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize patients who recover, yet these responses progress to NF-κB activation against non-structural proteins in patients who go on to experience poor clinical outcomes.
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Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.
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Acetamidas/farmacología , Células Epiteliales Alveolares/efectos de los fármacos , Ciclohexilaminas/farmacología , Proteostasis/efectos de los fármacos , Fibrosis Pulmonar/tratamiento farmacológico , Acetamidas/uso terapéutico , Factores de Edad , Células Epiteliales Alveolares/citología , Animales , Amianto , Bleomicina , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ciclohexilaminas/uso terapéutico , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/fisiología , Ratones , Ratones Endogámicos C57BL , Proteostasis/fisiología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Estrés Fisiológico/efectos de los fármacosRESUMEN
Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.
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Envejecimiento/inmunología , Microambiente Celular/inmunología , Pulmón/inmunología , Macrófagos Alveolares/inmunología , Envejecimiento/patología , Animales , Humanos , Pulmón/patología , Macrófagos Alveolares/patología , Ratones , Ratones Transgénicos , RNA-SeqRESUMEN
Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that IL-1ß production by donor NCM was responsible for the early activation of AM and CCL2 release. IL-1ß production by NCM was NLRP3 inflammasome dependent and inhibited by treatment with a clinically approved sulphonylurea. Production of CCL2 in the donor AM occurred through IL-1R-dependent activation of the PKC and NF-κB pathway. Accordingly, we show that IL-1ß-dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL-1ß, or IL-1R antagonism and inflammasome inhibition abrogated recruitment of CM and PGD and are feasible using FDA-approved compounds, our findings may have potential for clinical translation.
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Trasplante de Pulmón , Macrófagos Alveolares/inmunología , Monocitos/inmunología , Daño por Reperfusión/inmunología , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Disfunción Primaria del InjertoRESUMEN
BACKGROUND: Little is known about the use and burden of emergency department (ED) visits for cellulitis/erysipelas in the United States. OBJECTIVE: To determine the prevalence, risk factors, complications, and cost of emergency care for cellulitis/erysipelas in the United States. METHODS: Cross-sectional study of the 2006 to 2016 National Emergency Department Sample, including a 20% sample of US ED visits (N = 320,080,467). RESULTS: The mean annual incidence of ED visits with a primary diagnosis of cellulitis/erysipelas was 2.42 to 3.55 per million adult and 1.14 to 2.09 per million pediatric ED visits. ED visits for cellulitis/erysipelas decreased significantly from 2006 to 2015 (Rao-Scott chi-square, P < .0001). ED visits with versus without a primary diagnosis of cellulitis/erysipelas were associated with public or no insurance and lower household income quartiles, and were more likely to occur during weekends and summer months. The mean cost of ED visits for cellulitis/erysipelas more than doubled in adults (from $720 to $1680) and tripled in children (from $939 to $2,823) from 2006 to 2016. ED visits for cellulitis/erysipelas were associated with multiple risk factors and increased infectious complications. LIMITATIONS: No data on cellulitis and erysipelas treatment or recurrence. CONCLUSION: There is a substantial and increasing burden of ED visits for cellulitis/erysipelas in the United States. Many ED visits occurred for uncomplicated cellulitis/erysipelas, in part because of health care disparities.
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Celulitis (Flemón)/epidemiología , Costo de Enfermedad , Servicio de Urgencia en Hospital/estadística & datos numéricos , Erisipela/epidemiología , Aceptación de la Atención de Salud/estadística & datos numéricos , Celulitis (Flemón)/complicaciones , Celulitis (Flemón)/economía , Celulitis (Flemón)/microbiología , Niño , Estudios Transversales , Servicio de Urgencia en Hospital/economía , Servicio de Urgencia en Hospital/tendencias , Erisipela/complicaciones , Erisipela/economía , Erisipela/microbiología , Costos de la Atención en Salud/estadística & datos numéricos , Costos de la Atención en Salud/tendencias , Humanos , Incidencia , Persona de Mediana Edad , Factores de Riesgo , Estados Unidos/epidemiologíaAsunto(s)
Atención Ambulatoria/economía , Dermatitis Atópica/economía , Dermatitis Atópica/terapia , Servicio de Urgencia en Hospital/economía , Adulto , Niño , Dermatitis Atópica/diagnóstico , Femenino , Humanos , Masculino , Servicio Ambulatorio en Hospital/economía , Pacientes Ambulatorios/estadística & datos numéricos , Admisión del Paciente/economía , Estados UnidosRESUMEN
Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging. Bone marrow chimeric mice revealed that neutrophils were recruited by TRAM through activation of TLR4 in a MyD88-dependent manner. Intriguingly, low levels of endotoxin, insufficient to cause donor lung injury, promoted TRAM-dependent production of CXCL2, increased neutrophil recruitment, and led to PGD, which was independent of donor NCMs. Reactive oxygen species (ROS) increased in human donor lungs starting from the warm-ischemia phase and were associated with increased transcription and translocation to the plasma membrane of TLR4 in donor TRAMs. Consistently, scavenging ROS or inhibiting their production to prevent TLR4 transcription/translocation or blockade of TLR4 or coreceptor CD14 on donor TRAMs prevented neutrophil recruitment in response to endotoxin and ameliorated PGD. Our studies demonstrate that residual endotoxin after successful treatment of donor bacterial pneumonia promotes PGD through ischemia/reperfusion-primed donor TRAMs.
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Endotoxinas/toxicidad , Lesión Pulmonar/inmunología , Trasplante de Pulmón , Macrófagos Alveolares/inmunología , Disfunción Primaria del Injerto/inmunología , Daño por Reperfusión/inmunología , Animales , Humanos , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/genética , Lesión Pulmonar/patología , Macrófagos Alveolares/patología , Ratones , Ratones Transgénicos , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Neutrófilos/patología , Disfunción Primaria del Injerto/inducido químicamente , Disfunción Primaria del Injerto/genética , Disfunción Primaria del Injerto/patología , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunologíaRESUMEN
BACKGROUND: Atopic dermatitis (AD) is associated with altered skin barrier, microbiome, and immune dysregulation that may increase risk of skin infections. OBJECTIVE: The aim of the study was to determine whether AD is associated with skin infections and related outcomes. METHODS: Data from the 2006 to 2012 National Emergency Department Sample were analyzed, including an approximately 20% sample of all US emergency department (ED) visits (N = 198,102,435 adults or children). RESULTS: Skin infections were increased in ED visits of adults (7.14% vs 3.76%) and children (5.15% vs 2.48%) with AD. In multivariable logistic regression models, AD was associated with significantly higher odds of skin infection in adults (adjusted odds ratio [95% confidence interval] = 1.93 [1.89-1.97]) and children (2.23 [2.16-2.31]). Pediatric and adult AD were associated with significantly higher odds of carbuncle/furuncles, impetigo, cellulitis, erysipelas, methicillin-resistant and methicillin-sensitive Staphylococcus aureus infections, molluscum contagiosum, cutaneous warts, herpes simplex and zoster viruses, eczema herpeticum, dermatophytosis, and candidiasis of skin/nails and vulva/urogenitals. Adults with AD had significantly higher odds of genital warts (1.51 [1.36-1.52]) and herpes (1.23 [1.11-1.35]). Skin infections were associated with US $19 million excess annual costs of ED care in persons with AD. CONCLUSIONS: Atopic dermatitis patients had higher odds of multiple bacterial, viral, fungal, and sexually transmitted skin infections.
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Dermatitis Atópica/epidemiología , Dermatomicosis/epidemiología , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades Cutáneas Bacterianas/epidemiología , Enfermedades Cutáneas Virales/epidemiología , Adolescente , Adulto , Niño , Preescolar , Dermatomicosis/economía , Servicio de Urgencia en Hospital , Femenino , Costos de la Atención en Salud/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Enfermedades de Transmisión Sexual/economía , Enfermedades Cutáneas Bacterianas/economía , Enfermedades Cutáneas Virales/economía , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Patients with dermatomyositis have multiple risk factors for serious and opportunistic infections, including immune dysregulation, long-term systemic corticosteroid treatment and comorbid health conditions. We sought to determine whether dermatomyositis is associated with increased odds and burden of systemic, opportunistic and antibiotic-resistant infections. We analyzed data from the Nationwide Inpatient Sample from 2002 to 2012, containing a cross-sectional representative 20% sample of all hospitalizations in the US. Overall, dermatomyositis was associated with serious infections in adults (multivariable logistic regression; adjusted odds ratio [95% confidence interval]: 2.19 [2.08-2.30]) and children (1.45 [1.20-1.76]). In particular, dermatomyositis was significantly associated with 32 of 48 and 15 of 48 infections examined in adults and children, respectively, including infections of skin, bone, joints, brain, heart, lungs, and gastrointestinal system, as well sepsis, antibiotic-resistant and opportunistic infections. Predictors of infections included non-white race/ethnicity, insurance status, history of long-term systemic corticosteroid usage, Cushing's syndrome (likely secondary to corticosteroid usage), diabetes, and cancer. Serious infections were associated with significantly increased inpatient cost and death in dermatomyositis patients. In conclusion, dermatomyositis is associated with higher odds, costs and inpatient mortality from serious and opportunistic infections.