Severe Hyponatremia (96 mmol/L) Secondary to Primary Polydipsia and Pneumonia.

A 63-year-old man who presented to the hospital with altered mental status and decreased responsiveness was found to have severe symptomatic hyponatremia with a sodium level of 96 mmol/L and pneumonia. The patient was admitted to the medical intensive care unit for septic shock and acute severe hyponatremia. He was intubated for airway protection, and treated with 3% hypertonic saline bolus and antibiotics. After four days, sodium levels were corrected to 128 mmol/L, and the patient was extubated and downgraded to the medical floor. This case demonstrates one of the lowest recorded sodium lab values ever and the patient was successfully treated and discharged home with appropriate outpatient appointments.

Cell Type Catalog of Middle Turbinate Epithelium (Cell Catalog of Turbinate Epithelium).

Objective: Single-cell RNA-sequencing of middle turbinate mucosa was performed to create the first single-cell transcriptome catalog of this part of the human body. Study Design: Basic science research. Setting: Single center, tertiary care center. Methods: Samples were obtained from the head of the middle turbinate from a healthy volunteer. After the specimen was prepared per lab protocol, cells were dissociated, resuspended, and counted. Single-cell libraries were then prepared according to the 10x Genomics protocol and sequenced using NovaSeq 6000 (Illumina). Sequencing data were processed using Cell Ranger, and clustering and gene expression analysis was performed using Seurat. Cell types were annotated through expression profiling of single cells using known markers and data from other single-cell studies. Results: Fourteen unique cell types were identified, including serous, goblet, club, basal, ciliated, endothelial, and mesenchymal cells, as well as multiple types of blood cells. Conclusion: This catalog provides a comprehensive depiction of the cellular composition of middle turbinate mucosa. By uncovering the cellular stratification of gene expression profiles in the healthy middle turbinate epithelium, the groundwork has been laid for further investigation into the molecular pathogenesis and targeted therapy of sinonasal disease.

Small-Molecule Activation of Protein Phosphatase 2A Counters Bleomycin-Induced Fibrosis in Mice.

The activity of protein phosphatase 2A (PP2A), a serine-threonine phosphatase, is reduced in the lung fibroblasts of idiopathic pulmonary fibrosis (IPF) patients. The objective of this study was to determine whether the reactivation of PP2A could reduce fibrosis and preserve the pulmonary function in a bleomycin (BLM) mouse model. Here, we present a new class of direct small-molecule PP2A activators, diarylmethyl-pyran-sulfonamide, exemplified by ATUX-1215. ATUX-1215 has improved metabolic stability and bioavailability compared to our previously described PP2A activators. Primary human lung fibroblasts were exposed to ATUX-1215 and an older generation PP2A activator in combination with TGFß. ATUX-1215 treatment enhanced the PP2A activity, reduced the phosphorylation of ERK and JNK, and reduced the TGFß-induced expression of ACTA2, FN1, COL1A1, and COL3A1. C57BL/6J mice were administered 5 mg/kg ATUX-1215 daily following intratracheal instillation of BLM. Three weeks later, forced oscillation and expiratory measurements were performed using the Scireq Flexivent System. ATUX-1215 prevented BLM-induced lung physiology changes, including the preservation of normal PV loop, compliance, tissue elastance, and forced vital capacity. PP2A activity was enhanced with ATUX-1215 and reduced collagen deposition within the lungs. ATUX-1215 also prevented the BLM induction of Acta2, Ccn2, and Fn1 gene expression. Treatment with ATUX-1215 reduced the phosphorylation of ERK, p38, JNK, and Akt and the secretion of IL-12p70, GM-CSF, and IL1α in BLM-treated animals. Delayed treatment with ATUX-1215 was also observed to slow the progression of lung fibrosis. In conclusion, our study indicates that the decrease in PP2A activity, which occurs in fibroblasts from the lungs of IPF subjects, could be restored with ATUX-1215 administration as an antifibrotic agent.

Cultured Mesenchymal Cells from Nasal Turbinate as a Cellular Model of the Neurodevelopmental Component of Schizophrenia Etiology.

The study of neurodevelopmental molecular mechanisms in schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously utilized cell lines with neural progenitor properties (CNON) derived from the superior or middle turbinates of patients with schizophrenia and control groups to study schizophrenia-specific gene expression. In this study, we analyzed single-cell RNA seq data from two CNON cell lines (one derived from an individual with schizophrenia (SCZ) and the other from a control group) and two biopsy samples from the middle turbinate (MT) (also from an individual with SCZ and a control). We compared our data with previously published data regarding the olfactory neuroepithelium and demonstrated that CNON originated from a single cell type present both in middle turbinate and the olfactory neuroepithelium and expressed in multiple markers of mesenchymal cells. To define the relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data derived from an embryonic brain and found that the expression profile of the CNON closely matched the expression profile one of the cell types in the embryonic brain. Finally, we evaluated the differences between SCZ and control samples to assess the utility and potential benefits of using CNON single-cell RNA seq to study the etiology of schizophrenia.

Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Emphysema.

The activity of PP2A (protein phosphatase 2A), a serine-threonine phosphatase, is reduced by chronic cigarette smoke (SM) exposure and α-1 antitrypsin (AAT) deficiency, and chemical activation of PP2A reduces the loss of lung function in SM-exposed mice. However, the previously studied PP2A-activator tricyclic sulfonamide compound DBK-1154 has low stability to oxidative metabolism, resulting in fast clearance and low systemic exposure. Here we compare the utility of a new more stable PP2A activator, ATUX-792, versus DBK-1154 for the treatment of SM-induced emphysema. ATUX-792 was also tested in human bronchial epithelial cells and a mouse model of AAT deficiency, Serpina1a-e-knockout mice. Human bronchial epithelial cells were treated with ATUX-792 or DBK-1154, and cell viability, PP2A activity, and MAP (mitogen-activated protein) kinase phosphorylation status were examined. Wild-type mice received vehicle, DBK-1154, or ATUX-792 orally in the last 2 months of 4 months of SM exposure, and 8-month-old Serpina1a-e-knockout mice received ATUX-792 daily for 4 months. Forced oscillation and expiratory measurements and histology analysis were performed. Treatment with ATUX-792 or DBK-1154 resulted in PP2A activation, reduced MAP kinase phosphorylation, immune cell infiltration, reduced airspace enlargements, and preserved lung function. Using protein arrays and multiplex assays, PP2A activation was observed to reduce AAT-deficient and SM-induced release of CXCL5, CCL17, and CXCL16 into the airways, which coincided with reduced neutrophil lung infiltration. Our study indicates that suppression of the PP2A activity in two models of emphysema could be restored by next-generation PP2A activators to impact lung function.

Cultured Mesenchymal Cells from Nasal Turbinate as a Cellular Model of the Neurodevelopmental Component of Schizophrenia Etiology.

Study of the neurodevelopmental molecular mechanisms of schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously used cell lines with neural progenitor properties (CNON) derived from superior or middle turbinates of patients with schizophrenia and control groups to study gene expression specific to schizophrenia. In this study, we compared single cell-RNA seq data from two CNON cell lines, one derived from an individual with schizophrenia (SCZ) and the other from a control group, with two biopsy samples from the middle turbinate (MT), also from an individual with SCZ and a control. In addition, we compared our data with previously published data from olfactory neuroepithelium (1). Our data demonstrated that CNON originated from a single cell type which is present both in middle turbinate and olfactory neuroepithelium. CNON express multiple markers of mesenchymal cells. In order to define relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data of embryonic brain (2) and found that the expression profile of CNON very closely matched one of the cell types in the embryonic brain. Finally, we evaluated differences between SCZ and control samples to assess usability and potential benefits of using single cell RNA-seq of CNON to study etiology of schizophrenia.

Lung Function in Women With and Without Human Immunodeficiency Virus.

BACKGROUND: Prior studies have found that human immunodeficiency virus (HIV) infection is associated with impaired lung function and increased risk of chronic lung disease, but few have included large numbers of women. In this study, we investigate whether HIV infection is associated with differences in lung function in women. METHODS: This was a cross-sectional analysis of participants in the Women's Interagency HIV Study, a racially and ethnically diverse multicenter cohort of women with and without HIV. In 2018-2019, participants at 9 clinical sites were invited to perform spirometry. Single-breath diffusing capacity for carbon monoxide (DLCO) was also measured at selected sites. The primary outcomes were the post-bronchodilator forced expiratory volume in 1 second (FEV1) and DLCO. Multivariable regression modeling was used to analyze the association of HIV infection and lung function outcomes after adjustment for confounding exposures. RESULTS: FEV1 measurements from 1489 women (1062 with HIV, 427 without HIV) and DLCO measurements from 671 women (463 with HIV, 208 without HIV) met standards for quality and reproducibility. There was no significant difference in FEV1 between women with and without HIV. Women with HIV had lower DLCO measurements (adjusted difference, -0.73 mL/min/mm Hg; 95% confidence interval, -1.33 to -.14). Among women with HIV, lower nadir CD4 + cell counts and hepatitis C virus infection were associated with lower DLCO measurements. CONCLUSIONS: HIV was associated with impaired respiratory gas exchange in women. Among women with HIV, lower nadir CD4 + cell counts and hepatitis C infection were associated with decreased respiratory gas exchange.

Comparing the demographics and laboratory biomarkers of the COVID-19 Omicron wave and the Alpha wave in a predominantly Afro-Caribbean patient population in New York City.

BACKGROUND: There is a knowledge gap of specific characteristics linked to disease severity of the different COVID-19 waves, especially in underserved populations. We compared the demographic and clinical factors associated with SARS-CoV-2-infected patients admitted to the intensive care unit (ICU) during the Omicron and Alpha waves. METHODS: An observational study comparing two COVID-19 waves was conducted in Brooklyn, NY. Twenty-seven ICU admitted patients with a positive COVID-19 test result during the period of November 1, 2021, to January 31, 2022, ("Omicron wave") were compared to 271 COVID-19 patients who received ICU consults during the Alpha wave, the period from March 28, 2020, to April 30, 2020. RESULTS: The Omicron wave had a 55.6% mortality rate compared to a 67.2% mortality rate in the Alpha wave. For the non-survivors, there were more females (66.7%) in the Omicron wave, while the trend was reversed in the Alpha wave (38.5%). Most of the patients seen were Black (> 85%) in both waves. A bivariate comparison of the two waves found that patients in the Omicron wave had overall significantly lower ALT levels (p = 0.03) and higher monocyte % (p = 0.005) compared to the patients in the Alpha wave. In the multivariate analysis, adjusting for age and sex, increasing levels of HCO3- were significantly associated with reduced mortality in the Omicron wave (OR: 0.698; 95% CI: 0.516 - 0.945; p = 0.02). Also, multivariable analyses using both waves combined found that neutrophil % was significantly associated with increased mortality (OR: 1.05; 95% CI: 1.02 - 1.09; p = 0.006) while lymphocyte % was significantly associated with reduced mortality (OR: 0.946; 95% CI: 0.904 - 0.990; p = 0.018). CONCLUSIONS: The COVID-19-positive ICU patients in the Omicron wave experienced less severe outcomes than those of the Alpha wave. In contrast to the Alpha variant, the Omicron variant exhibited enhanced infectivity and disease severity in females.

Association Between HIV and Prevalence and Manifestations of Asthma: Analysis of the Multicenter AIDS Cohort Study and Women's Interagency HIV Study.

BACKGROUND: The association between HIV and asthma prevalence and manifestations remains unclear, with few studies including women. SETTING: A retrospective observational cohort study from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. METHODS: Asthma was defined in 2 ways: (1) self-report and (2) robust criteria requiring all the following: lack of fixed airflow obstruction, presence of wheeze on the St. George's Respiratory Questionnaire (SGRQ), and report of asthma therapies. Estimates of asthma prevalence and asthma-related manifestations were compared by HIV serostatus. RESULTS: A total of 1815 men and 2122 women were included. Asthma prevalence did not differ between people with HIV (PWH) and people without HIV regardless of definition: self-report (men, 12.0% vs. 11.2%; women, 24.3% vs. 27.5%) and robust criteria (men, 5.0% vs. 3.4%; women, 12.8% vs. 13.2%). Among men with asthma, worse respiratory symptom burden was reported among those with HIV, regardless of asthma definition. Among women with self-reported asthma, those with HIV had less respiratory symptom burden. Regardless of serostatus, women with robust-defined asthma had similar respiratory symptoms across SGRQ domains and similar frequencies of phlegm, shortness of breath, and wheezing. CONCLUSIONS: Among PWH and people without HIV, asthma prevalence was 2-fold to 3-fold higher using self-reported definition rather than robust definition. In men and women, HIV was not associated with increased asthma prevalence. In men, HIV was associated with more respiratory symptoms when asthma was self-reported; the relationship was attenuated with the robust criteria. Further studies are needed to explore asthma phenotypes among PWH.

Pulmonary Function Trajectories in People with HIV: Analysis of the Pittsburgh HIV Lung Cohort.

Rationale: Human immunodeficiency virus (HIV) infection is associated with chronic lung disease and impaired pulmonary function; however, longitudinal pulmonary function phenotypes in HIV are undefined. Objectives: To identify pulmonary function trajectories, their determinants, and outcomes. Methods: We used data from participants with HIV in the Pittsburgh HIV Lung Cohort with three or more pulmonary function tests between 2007 and 2020. We analyzed post-bronchodilator forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC, and diffusing capacity of the lung for carbon monoxide (DlCO) using group-based trajectory modeling to identify subgroups of individuals whose measurements followed a similar pattern over time. We examined the association between participant characteristics and trajectories using multivariable logistic regression. In exploratory adjusted analyses restricted to individuals with available plasma cytokine data, we investigated the association between 18 individual standardized cytokine concentrations and trajectories. We compared mortality, dyspnea prevalence, respiratory health status, and 6-minute-walk distance between phenotypes. Results: A total of 265 participants contributed 1,606 pulmonary function measurements over a median follow-up of 8.1 years. We identified two trajectories each for FEV1 and FVC: "low baseline, slow decline" and "high baseline, rapid decline." There were three trajectory groups for FEV1/FVC: "rapid decline," "moderate decline," and "slow decline." Finally, we identified two trajectories for DlCO: "baseline low" and "baseline high." The low baseline, slow decline FEV1 and FVC, rapid decline, and moderate decline FEV1/FVC, and baseline low DlCO phenotypes were associated with increased dyspnea prevalence, worse respiratory health status, and decreased 6-minute-walk distance. The baseline low DlCO phenotype was also associated with worse mortality. Current smoking and pack-years of smoking were associated with the adverse FEV1, FEV1/FVC, and DlCO phenotypes. Detectable viremia was the only HIV marker associated with the adverse DlCO phenotype. C-reactive protein and endothelin-1 were associated with the adverse FEV1 and FVC phenotypes, and endothelin-1 trended toward an association with the adverse DlCO phenotype. Conclusions: We identified novel, distinct longitudinal pulmonary function phenotypes with significant differences in characteristics and outcomes. These findings highlight the importance of lung dysfunction over time in people with HIV and should be validated in additional cohorts.

LRP1 loss in airway epithelium exacerbates smoke-induced oxidative damage and airway remodeling.

The LDL receptor-related protein 1 (LRP1) partakes in metabolic and signaling events regulated in a tissue-specific manner. The function of LRP1 in airways has not been studied. We aimed to study the function of LRP1 in smoke-induced disease. We found that bronchial epithelium of patients with chronic obstructive pulmonary disease and airway epithelium of mice exposed to smoke had increased LRP1 expression. We then knocked out LRP1 in human bronchial epithelial cells in vitro and in airway epithelial club cells in mice. In vitro, LRP1 knockdown decreased cell migration and increased transforming growth factor ß activation. Tamoxifen-inducible airway-specific LRP1 knockout mice (club Lrp1-/-) induced after complete lung development had increased inflammation in the bronchoalveolar space and lung parenchyma at baseline. After 6 months of smoke exposure, club Lrp1-/- mice showed a combined restrictive and obstructive phenotype, with lower compliance, inspiratory capacity, and forced expiratory volume0.05/forced vital capacity than WT smoke-exposed mice. This was associated with increased values of Ashcroft fibrotic index. Proteomic analysis of room air exposed-club Lrp1-/- mice showed significantly decreased levels of proteins involved in cytoskeleton signaling and xenobiotic detoxification as well as decreased levels of glutathione. The proteome fingerprint created by smoke eclipsed many of the original differences, but club Lrp1-/- mice continued to have decreased lung glutathione levels and increased protein oxidative damage and airway cell proliferation. Therefore, LRP1 deficiency leads to greater lung inflammation and damage and exacerbates smoke-induced lung disease.

Procalcitonin Levels in COVID-19 Patients Are Strongly Associated with Mortality and ICU Acceptance in an Underserved, Inner City Population.

Background and Objectives: This study aimed to identify demographic and clinical factors at the time of critical care consultation associated with mortality or intensive care unit acceptance in a predominantly Afro-Caribbean population during the first wave of the COVID19 pandemic. Materials and Methods: This retrospective, single-center observational cohort study included 271 COVID19 patients who received a critical care consult between March 11 and April 30, 2020 during the first wave of the COVID19 pandemic at State University of New York Downstate Health Sciences University. Results: Of the 271 patients with critical care consults, 33% survived and 67% expired. At the bivariate level, age, blood urea nitrogen, and blood neutrophil percentage were significantly associated with mortality (mean age: survivors, 61.62 ± 1.50 vs. non-survivors, 68.98 ± 0.85, p < 0.001). There was also a significant association between neutrophil% and mortality in the univariate logistic regression model (quartile 4 vs. quartile 1: odd ratio 2.73, 95% confidence interval (1.28-5.82), p trend = 0.044). In the multivariate analyses, increasing levels of procalcitonin and C-reactive protein were significantly associated with mortality, adjusting for age, sex, and race/ethnicity (for procalcitonin quartile 4 vs. quartile 1: odds ratio 5.65, 95% confidence interval (2.14-14.9), p trend < 0.001). In contrast, higher platelet levels correlated with significantly decreased odds of mortality (quartile 4 vs. quartile 1, odds ratio 0.47, 95% CI (0.22-0.998), p trend = 0.010). Of these factors, only elevated procalcitonin levels were associated with intensive care unit acceptance. Conclusions: Procalcitonin showed the greatest magnitude of association with both death and likelihood of intensive care unit acceptance at the bivariate level. Our data suggests that procalcitonin reflects pneumonia severity during COVID-19 infection. Thus, it may help the intensivist identify those COVID19 patients who require intensive care unit level care.

Systemic inflammation and protease profile of Afro-Caribbean patients with sepsis.

OBJECTIVES: Sepsis is one of the leading causes of morbidity and mortality within the healthcare system and remains a diagnostic and therapeutic challenge. A major issue in the diagnosis of sepsis is understanding the pathophysiologic mechanism, which revolves around host immune system activation and dysregulated responses. African Americans are more likely to experience severe sepsis with higher mortality rates compared to the general population. This pilot study characterized multiple inflammatory markers and proteases in plasma of primarily African American and Afro-Caribbean patients with mild sepsis. METHODS: Plasma was collected from 16 healthy controls and 15 subjects presenting with sepsis, on admission, and again upon resolution of the signs of sepsis, defined as a resolution of sepsis criteria. Plasma samples were analyzed for cytokines, chemokines, and proteases using multiplex bead assays. RESULTS: Elevated levels of granulocyte colony-stimulating factor, interleukin-10, interleukin-15, interleukin-1 receptor antagonist, interleukin-8, interferon gamma-induced protein 10, monocyte chemoattractant protein-1, matrix metallopeptidase 12, and cathepsin S were identified in plasma from sepsis patients on admission compared to control subjects. Interleukin-6, interleukin-8, granulocyte colony-stimulating factor, and cathepsin S were reduced in sepsis patients upon clinical resolution of sepsis. CONCLUSION: These findings profile the circulating inflammatory cytokines, chemokines, and proteases in African Americans and Afro-Caribbean patients during sepsis. The role of these targets in sepsis needs addressing in this patient population.

Balanced Wnt/Dickkopf-1 signaling by mesenchymal vascular progenitor cells in the microvascular niche maintains distal lung structure and function.

The well-described Wnt inhibitor Dickkopf-1 (DKK1) plays a role in angiogenesis as well as in regulation of growth factor signaling cascades in pulmonary remodeling associated with chronic lung diseases (CLDs) including emphysema and fibrosis. However, the specific mechanisms by which DKK1 influences mesenchymal vascular progenitor cells (MVPCs), microvascular endothelial cells (MVECs), and smooth muscle cells (SMCs) within the microvascular niche have not been elucidated. In this study, we show that knockdown of DKK1 in Abcg2pos lung mouse adult tissue resident MVPCs alters lung stiffness, parenchymal collagen deposition, microvessel muscularization and density as well as loss of tissue structure in response to hypoxia exposure. To complement the in vivo mouse modeling, we also identified cell- or disease-specific responses to DKK1, in primary lung chronic obstructive pulmonary disease (COPD) MVPCs, COPD MVECs, and SMCs, supporting a paradoxical disease-specific response of cells to well-characterized factors. Cell responses to DKK1 were dose dependent and correlated with varying expressions of the DKK1 receptor, CKAP4. These data demonstrate that DKK1 expression is necessary to maintain the microvascular niche whereas its effects are context specific. They also highlight DKK1 as a regulatory candidate to understand the role of Wnt and DKK1 signaling between cells of the microvascular niche during tissue homeostasis and during the development of chronic lung diseases.

Elevated S100A9 expression in chronic rhinosinusitis coincides with elevated MMP production and proliferation in vitro.

Chronic rhinosinusitis (CRS) is a common condition associated with inflammation and tissue remodeling of the nose and paranasal sinuses, frequently occurring with nasal polyps and allergies. Here we investigate inflammation and the protease profile in nasal tissues and plasma from control non-CRS patients and CRS patients. Gene expression for several cytokines, proteases, and antiproteases was quantified in nasal tissue from non-CRS and CRS subjects with nasal polyps. Elevated expression of S100A9, IL1A, MMP3, MMP7, MMP11, MMP25, MMP28, and CTSK was observed in tissue from CRS subjects with nasal polyps compared to control tissue. Tissue protein analysis confirmed elevated levels of these targets compared to controls, and increased MMP3 and MMP7 observed in CRS subjects with nasal polyps compared to CRS subjects without polyps. Plasma concentrations of MMP3 and MMP7 were elevated in the CRS groups compared to controls. The nasal cell line, CCL-30, was exposed to S100A9 protein, resulting in increased MMP3, MMP7, and CTSK gene expression and elevated proliferation. Silencing MMP3 significantly reduced S100A9-mediated cell proliferation. Therefore, the elevated expression of S100A9 and MMPs are observed in CRS nasal tissue and S100A9 stimulated MMP3 responses to contribute to elevated nasal cell proliferation.

Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease.

S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9-/- mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicle-administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD.

Elevated levels of calpain 14 in nasal tissue in chronic rhinosinusitis.

Sinusitis is a common condition associated with inflammation in the sinuses and nasal mucosa. Calpain 14 is highly expressed in the nasal tissues of sinusitis subjects. Calpain 14 is associated with epithelial barrier disruption. https://bit.ly/3fyAwVO.

SIRT7 deficiency suppresses inflammation, induces EndoMT, and increases vascular permeability in primary pulmonary endothelial cells.

Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases. We recently showed decreased SIRT7 expression in lung tissues and fibroblasts from patients with pulmonary fibrosis compared to controls. To gain insight into aging-related mechanisms in ALI, we investigated the effects of SIRT7 depletion on lipopolysaccharide (LPS)-induced inflammatory responses and endothelial barrier permeability in human primary pulmonary endothelial cells. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuated LPS-induced increases in ICAM1, VCAM1, IL8, and IL6 and induced endomesenchymal transition (EndoMT) with decreases in VE-Cadherin and PECAM1 and increases in collagen, alpha-smooth muscle actin, TGFß receptor 1, and the transcription factor Snail. Loss of endothelial adhesion molecules was accompanied by increased F-actin stress fibers and increased endothelial barrier permeability. Together, these results show that an aging phenotype induced by SIRT7 deficiency promotes EndoMT with impaired inflammatory responses and dysfunction of the lung vascular barrier.

Resident mesenchymal vascular progenitors modulate adaptive angiogenesis and pulmonary remodeling via regulation of canonical Wnt signaling.

Adaptive angiogenesis is necessary for tissue repair, however, it may also be associated with the exacerbation of injury and development of chronic disease. In these studies, we demonstrate that lung mesenchymal vascular progenitor cells (MVPC) modulate adaptive angiogenesis via lineage trace, depletion of MVPC, and modulation of ß-catenin expression. Single cell sequencing confirmed MVPC as multipotential vascular progenitors, thus, genetic depletion resulted in alveolar simplification with reduced adaptive angiogenesis. Following vascular endothelial injury, Wnt activation in MVPC was sufficient to elicit an emphysema-like phenotype characterized by increased MLI, fibrosis, and MVPC driven adaptive angiogenesis. Lastly, activation of Wnt/ß-catenin signaling skewed the profile of human and murine MVPC toward an adaptive phenotype. These data suggest that lung MVPC drive angiogenesis in response to injury and regulate the microvascular niche as well as subsequent distal lung tissue architecture via Wnt signaling.

Commentary on: The potency of lncRNA MALAT1/miR-155 in altering asthmatic Th1/Th2 balance by modulation of CTLA4.

Asthma is a common, allergic respiratory disorder affecting over 350 million people worldwide. One of the key features of asthma is skewing of CD4+ cells toward Th2 responses. This promotes the production of cytokines like IL-4 that induce IgE production resulting in the hypersecretion of mucus and airway smooth muscle contraction. Understanding the factors that favor Th2 expansion in asthma would provide important insights into the underlying pathogenesis of this disorder. Asthma research has focused on signaling pathways that control the transcription of key asthma-related genes. However, increasing evidence shows that post-transcriptional factors also determine CD4+ cell fate and the enhancement of allergic airway responses. A recent paper published by Liang et al. (Bioscience Reports (2020) 40, https://doi.org/10.1042/BSR20190397) highlights a novel role for the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in Th2 development in asthma. MALAT1 modulates several biological processes including alternative splicing, epigenetic modification and gene expression. It is one of the most highly expressed lncRNAs in normal tissues and MALAT1 levels correlate with poor clinical outcomes in cancer. The mechanisms of action of MALAT1 in tumor progression and metastasis remain unclear and even less is known about its effects in inflammatory disease states like asthma. The work of Liang et al. demonstrates heightened MALAT1 expression in asthma and further shows that this lncRNA targets miR-155 to promote Th2 differentiation in this disease. This insight sets the stage for future studies to examine how MALAT1 manipulation could deter allergic immune responses in asthmatic airways.