Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.

Adult stem cells play a crucial role in tissue homeostasis and repair through multiple mechanisms. In addition to being able to replace aged or damaged cells, stem cells provide signals that contribute to the maintenance and function of neighboring cells. In the lung, airway basal stem cells also produce cytokines and chemokines in response to inhaled irritants, allergens, and pathogens, which affect specific immune cell populations and shape the nature of the immune response. However, direct cell-to-cell signaling through contact between airway basal stem cells and immune cells has not been demonstrated. Recently, a unique population of intraepithelial airway macrophages (IAMs) has been identified in the murine trachea. Here, we demonstrate that IAMs require Notch signaling from airway basal stem cells for maintenance of their differentiated state and function. Furthermore, we demonstrate that Notch signaling between airway basal stem cells and IAMs is required for antigen-induced allergic inflammation only in the trachea where the basal stem cells are located whereas allergic responses in distal lung tissues are preserved consistent with a local circuit linking stem cells to proximate immune cells. Finally, we demonstrate that IAM-like cells are present in human conducting airways and that these cells display Notch activation, mirroring their murine counterparts. Since diverse lung stem cells have recently been identified and localized to specific anatomic niches along the proximodistal axis of the respiratory tree, we hypothesize that the direct functional coupling of local stem cell-mediated regeneration and immune responses permits a compartmentalized inflammatory response.

Intracranial self-stimulation reverses impaired spatial learning and regulates serum microRNA levels in a streptozotocin-induced rat model of Alzheimer disease.

BACKGROUND: The assessment of deep brain stimulation (DBS) as a therapeutic alternative for treating Alzheimer disease (AD) is ongoing. We aimed to determine the effects of intracranial self-stimulation at the medial forebrain bundle (MFB-ICSS) on spatial memory, neurodegeneration, and serum expression of microRNAs (miRNAs) in a rat model of sporadic AD created by injection of streptozotocin. We hypothesized that MFB-ICSS would reverse the behavioural effects of streptozotocin and modulate hippocampal neuronal density and serum levels of the miRNAs. METHODS: We performed Morris water maze and light-dark transition tests. Levels of various proteins, specifically amyloid-ß precurser protein (APP), phosphorylated tau protein (pTAU), and sirtuin 1 (SIRT1), and neurodegeneration were analyzed by Western blot and Nissl staining, respectively. Serum miRNA expression was measured by reverse transcription polymerase chain reaction. RESULTS: Male rats that received streptozotocin had increased hippocampal levels of pTAU S202/T205, APP, and SIRT1 proteins; increased neurodegeneration in the CA1, dentate gyrus (DG), and dorsal tenia tecta; and worse performance in the Morris water maze task. No differences were observed in miRNAs, except for miR-181c and miR-let-7b. After MFB-ICSS, neuronal density in the CA1 and DG regions and levels of miR-181c in streptozotocin-treated and control rats were similar. Rats that received streptozotocin and underwent MFB-ICSS also showed lower levels of miR-let-7b and better spatial learning than rats that received streptozotocin without MFB-ICSS. LIMITATIONS: The reversal by MFB-ICSS of deficits induced by streptozotocin was fairly modest. CONCLUSION: Spatial memory performance, hippocampal neurodegeneration, and serum levels of miR-let-7b and miR-181c were affected by MFB-ICSS under AD-like conditions. Our results validate the MFB as a potential target for DBS and lend support to the use of specific miRNAs as promising biomarkers of the effectiveness of DBS in combatting AD-associated cognitive deficits.

The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer.

BACKGROUND: The discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC. METHODS: Genetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models. RESULTS: PITPNC1 was increased in human LUAD and PDAC, and associated with poor patients' survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC. CONCLUSIONS: Our data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments.

A Longitudinal Exploration of How Connections to Staff Facilitate Efficacy and Service Use in Drop-in Centers Serving Youth Experiencing Homelessness.

INTRODUCTION: Youth experiencing homelessness (YEH) benefit from a variety of services to meet their immediate and long-term needs. Drop-in centers are a popular service venue used by YEH. However, the mechanisms responsible for engaging youth in drop-in services are not clear. The current study uses longitudinal data to explore the role of positive staff relationships in increasing youths' knowledge and efficacy to access and subsequently use drop-in center services. METHODS: 731 youth (Mage = 21.8, SD = 2.2, 25.1% female) accessing services at three drop-in centers in Los Angeles, California participated in the study. Surveys were completed at baseline, 1-month, and 3-months later. Path models examined the direct effect of positive relationships with adult staff on service use at the 3-month follow-up, and the indirect effect of service knowledge (assessed at the 1-month follow-up). RESULTS: The direct effect model showed that positive staff relationships at baseline were significantly associated with number of services used at the 3-month follow-up (aIRR = 1.24, 95% CI: 1.00, 1.54). Positive staff relationships were also associated with greater service knowledge at 1-month (b = 0.93, p < 0.001), which in turn was associated with greater service use at 3-months (IRR = 1.15, 95% CI: 1.04, 1.28). The indirect effect of service knowledge was significant (b = 0.13, p = 0.02), suggesting that the association between positive staff relationships and service use was completely mediated by service knowledge. CONCLUSIONS: The current study adds to the literature by demonstrating that positive relationships with staff lead to increased service use by increasing youths' knowledge and efficacy to access services. Efforts should be made to develop positive relationships with YEH in order to engage them in essential services needed to exit homelessness.

Intracranial Self-stimulation of the Medial Forebrain Bundle Ameliorates Memory Disturbances and Pathological Hallmarks in an Alzheimer's Disease Model by Intracerebral Administration of Amyloid-ß in Rats.

No curative or fully effective treatments are currently available for Alzheimer's disease (AD), the most common form of dementia. Electrical stimulation of deep brain areas has been proposed as a novel neuromodulatory therapeutic approach. Previous research from our lab demonstrates that intracranial self-stimulation (ICSS) targeting medial forebrain bundle (MFB) facilitates explicit and implicit learning and memory in rats with age or lesion-related memory impairment. At a molecular level, MFB-ICSS modulates the expression of plasticity and neuroprotection-related genes in memory-related brain areas. On this basis, we suggest that MFB could be a promising stimulation target for AD treatment. In this study, we aimed to assess the effects of MFB-ICSS on both explicit memory as well as the levels of neuropathological markers ptau and drebrin (DBN) in memory-related areas, in an AD rat model obtained by Aß icv-injection. A total of 36 male rats were trained in the Morris water maze on days 26-30 after Aß injection and tested on day 33. Results demonstrate that this Aß model displayed spatial memory impairment in the retention test, accompanied by changes in the levels of DBN and ptau in lateral entorhinal cortex and hippocampus, resembling pathological alterations in early AD. Administration of MFB-ICSS treatment consisting of 5 post-training sessions to AD rats managed to reverse the memory deficits as well as the alteration in ptau and DBN levels. Thus, this paper reports both cognitive and molecular effects of a post-training reinforcing deep brain stimulation procedure in a sporadic AD model for the first time.

Implementing patient safety and quality improvement in dermatology. Part 1: Patient safety science.

Patient safety (PS) and quality improvement (QI) have gained momentum over the last decade and are becoming more integrated into medical training, physician reimbursement, maintenance of certification, and practice improvement initiatives. While PS and QI are often lumped together, they differ in that PS is focused on preventing adverse events while QI is focused on continuous improvements to improve outcomes. The pillars of health care as defined by the 1999 Institute of Medicine report "To Err is Human: Building a Safer Health System" are safety, timeliness, effectiveness, efficiency, equity, and patient-centered care. Implementing a safety culture is dependent on all levels of the health care system. Part 1 of this CME will provide dermatologists with an overview of how PS fits into our current health care system and will include a focus on basic QI/PS terminology, principles, and processes. This article also outlines systems for the reporting of medical errors and sentinel events and the steps involved in a root cause analysis.

Implementing patient safety and quality improvement in dermatology. Part 2: Quality improvement science.

Quality improvement (QI) in medicine is reliant on a team-based approach and an understanding of core QI principles. Part 2 of this continuing medical education series outlines the steps of performing a QI project, from identifying QI opportunities, to carrying out successive Plan-Do-Study-Act cycles, to hard-wiring improvements into the system. QI frameworks will be explored and readers will understand how to interpret basic QI data.

Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis.

The lung epithelium is constantly exposed to harmful agents present in the air that we breathe making it highly susceptible to damage. However, in instances of injury to the lung, it exhibits a remarkable capacity to regenerate injured tissue thanks to the presence of distinct stem and progenitor cell populations along the airway and alveolar epithelium. Mechanisms of repair are affected in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF), a progressive life-threatening disorder characterized by the loss of alveolar structures, wherein excessive deposition of extracellular matrix components cause the distortion of tissue architecture that limits lung function and impairs tissue repair. Here, we review the most recent findings of a study of epithelial cells with progenitor behavior that contribute to tissue repair as well as the mechanisms involved in mouse and human lung regeneration. In addition, we describe therapeutic strategies to promote or induce lung regeneration and the cell-based strategies tested in clinical trials for the treatment of IPF. Finally, we discuss the challenges, concerns and limitations of applying these therapies of cell transplantation in IPF patients. Further research is still required to develop successful strategies focused on cell-based therapies to promote lung regeneration to restore lung architecture and function.

The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells.

Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved. Here, we show that CXCL12 produced by Prx1+ mesenchymal cells but not by mature osteolineage cells provide the necessary cues for the maintenance of LSCs in the marrow of an MLL::AF9-induced AML model. Prx1+ cells promote survival of LSCs by modulating energy metabolism and the REDOX balance in LSCs. Deletion of Cxcl12 leads to the accumulation of reactive oxygen species and DNA damage in LSCs, impairing their ability to perpetuate leukemia in transplantation experiments, a defect that can be attenuated by antioxidant therapy. Importantly, our data suggest that this phenomenon appears to be conserved in human patients. Hence, we have identified Prx1+ mesenchymal cells as an integral part of the complex niche-AML metabolic intertwining, pointing towards CXCL12/CXCR4 as a target to eradicate parenchymal LSCs in AML.

Fast fragment- and compound-screening pipeline at the Swiss Light Source.

Over the last two decades, fragment-based drug discovery (FBDD) has emerged as an effective and efficient method to identify new chemical scaffolds for the development of lead compounds. X-ray crystallography can be used in FBDD as a tool to validate and develop fragments identified as binders by other methods. However, it is also often used with great success as a primary screening technique. In recent years, technological advances at macromolecular crystallography beamlines in terms of instrumentation, beam intensity and robotics have enabled the development of dedicated platforms at synchrotron sources for FBDD using X-ray crystallography. Here, the development of the Fast Fragment and Compound Screening (FFCS) platform, an integrated next-generation pipeline for crystal soaking, handling and data collection which allows crystallography-based screening of protein crystals against hundreds of fragments and compounds, at the Swiss Light Source is reported.

MYPATH: A novel mindfulness and yoga-based peer leader intervention to prevent violence among youth experiencing homelessness.

Young adults experiencing homelessness (YAEH) are at elevated risk for violence victimization and perpetration. However, there are no evidence-based violence prevention interventions for homeless populations. This study is an evaluation of a novel mindfulness-based peer-leader intervention designed to reduce violence and improve mindfulness in YAEH. A social network of YAEH receiving services at a drop-in agency was recruited in Summer 2018 (n = 106) and peer-leaders identified at baseline (n = 12). Peer leaders were trained in mindfulness and yoga skills during a 1-day intensive workshop and seven 1-h weekly follow-up workshops and encouraged to share their knowledge with in-network peers. Postintervention data were collected 2 and 3 months after baseline. Two one-way repeated-measures analyses of variance (ANOVAs) tested differences in means for mindfulness and fighting. ANOVA models showed significant increases in group mean mindfulness F(2, 110) = 3.42, p < 0.05 and significant decreases in group mean violent behavior F(2, 112) = 5.23, p < 0.01 at the network level. Findings indicate a network-based, peer-leader model can be effective for influencing complex, socially conditioned attitudes and behaviors among YAEH. Additional advantages of the peer-leader model include relatively few direct-service person-hours required from providers and convenience to participants able practice skills in their relevant social contexts.

Protocol to assess rewarding brain stimulation as a learning and memory modulating treatment: Comparison between self-administration and experimenter-administration.

Intracranial electrical self-stimulation (ICSS) is a useful procedure in animal research. This form of administration ensures that areas of the brain reward system (BRS) are being functionally activated, since the animals must perform an operant response to self-administer an electrical stimulus. Rewarding post-training ICSS of the medial forebrain bundle (MFB), an important system of the BRS, has been shown to consistently improve rats' acquisition and retention in several learning tasks. In the clinical setting, deep brain stimulation (DBS) of different targets is currently being used to palliate the memory impairment that occurs in some neurodegenerative diseases. However, the stimulation of the MFB has only been used to treat emotional alterations, not memory disorders. Since DBS stimulation treatments in humans are exclusively administered by external sources, studies comparing the efficacy of that form of application to a self-administered stimulation are key to the translationality of ICSS. This protocol compares self-administered (ICSS) and experimenter-administered (EAS) stimulation of the MFB on the spatial Morris Water Maze task (MWM). c-Fos immunohistochemistry procedure was carried out to evaluate neural activation after retention. Results show that the stimulation of the MFB improves the MWM task regardless of the form of administration, although some differences in c-Fos expression were found. Present results suggest that MFB-ICSS is a valid animal model to study the effects of MFB electrical stimulation on memory, which could guide clinical applications of DBS. The present protocol is a useful guide for establishing ICSS behavior in rats, which could be used as a learning and memory-modulating treatment.

A Peer-Led, Artificial Intelligence-Augmented Social Network Intervention to Prevent HIV Among Youth Experiencing Homelessness.

BACKGROUND: Youth experiencing homelessness (YEH) are at elevated risk of HIV/AIDS and disproportionately identify as racial, ethnic, sexual, and gender minorities. We developed a new peer change agent (PCA) HIV prevention intervention with 3 arms: (1) an arm using an artificial intelligence (AI) planning algorithm to select PCAs; (2) a popularity arm, the standard PCA approach, operationalized as highest degree centrality (DC); and (3) an observation-only comparison group. SETTING: A total of 713 YEH were recruited from 3 drop-in centers in Los Angeles, CA. METHODS: Youth consented and completed a baseline survey that collected self-reported data on HIV knowledge, condom use, and social network information. A quasi-experimental pretest/posttest design was used; 472 youth (66.5% retention at 1 month postbaseline) and 415 youth (58.5% retention at 3 months postbaseline) completed follow-up. In each intervention arm (AI and DC), 20% of youth was selected as PCAs and attended a 4-hour initial training, followed by 7 weeks of half-hour follow-up sessions. Youth disseminated messages promoting HIV knowledge and condom use. RESULTS: Using generalized estimating equation models, there was a significant reduction over time (P < 0.001) and a significant time by AI arm interaction (P < 0.001) for condomless anal sex act. There was a significant increase in HIV knowledge over time among PCAs in DC and AI arms. CONCLUSIONS: PCA models that promote HIV knowledge and condom use are efficacious for YEH. Youth are able to serve as a bridge between interventionists and their community. Interventionists should consider working with computer scientists to solve implementation problems.

Pink-beam serial femtosecond crystallography for accurate structure-factor determination at an X-ray free-electron laser.

Serial femtosecond crystallography (SFX) at X-ray free-electron lasers (XFELs) enables essentially radiation-damage-free macromolecular structure determination using microcrystals that are too small for synchrotron studies. However, SFX experiments often require large amounts of sample in order to collect highly redundant data where some of the many stochastic errors can be averaged out to determine accurate structure-factor amplitudes. In this work, the capability of the Swiss X-ray free-electron laser (SwissFEL) was used to generate large-bandwidth X-ray pulses [Δλ/λ = 2.2% full width at half-maximum (FWHM)], which were applied in SFX with the aim of improving the partiality of Bragg spots and thus decreasing sample consumption while maintaining the data quality. Sensitive data-quality indicators such as anomalous signal from native thaumatin micro-crystals and de novo phasing results were used to quantify the benefits of using pink X-ray pulses to obtain accurate structure-factor amplitudes. Compared with data measured using the same setup but using X-ray pulses with typical quasi-monochromatic XFEL bandwidth (Δλ/λ = 0.17% FWHM), up to fourfold reduction in the number of indexed diffraction patterns required to obtain similar data quality was achieved. This novel approach, pink-beam SFX, facilitates the yet underutilized de novo structure determination of challenging proteins at XFELs, thereby opening the door to more scientific breakthroughs.

Financial distress/well-being and living situation in Ecuadorian health workers.

The tendency to live alone is a relatively recent phenomenon in Ecuador, but it is expanding rapidly. This study aims to identify factors associated with financial distress/well-being according to living situation (living alone vs. living with a partner) in Ecuadorian health workers. This study examined the construct of financial distress/well-being in a sample of 800 Ecuadorian health workers using cross-sectional data. Living situation was compared using generalized linear model analyses including income, age, children living at home, self-perception of health, depression, anxiety and stress, perceived social support, positive mental health, and hedonistic and austere profiles. Regarding financial well-being, workers living alone ranked lower and workers living with a partner ranked higher. In workers living alone the main sources of financial distress/well-being were income, children living at home, perceived social support, positive mental health, and hedonistic attitude towards indebtedness. In workers living with a partner the main sources of financial distress/well-being were income, age, self-perception of health, depression, anxiety and stress, perceived social support, positive mental health, and austere attitude towards indebtedness. Based on our results, we discuss potential public policy interventions that can be used to improve workers' financial well-being.

Versatile microporous polymer-based supports for serial macromolecular crystallography.

Serial data collection has emerged as a major tool for data collection at state-of-the-art light sources, such as microfocus beamlines at synchrotrons and X-ray free-electron lasers. Challenging targets, characterized by small crystal sizes, weak diffraction and stringent dose limits, benefit most from these methods. Here, the use of a thin support made of a polymer-based membrane for performing serial data collection or screening experiments is demonstrated. It is shown that these supports are suitable for a wide range of protein crystals suspended in liquids. The supports have also proved to be applicable to challenging cases such as membrane proteins growing in the sponge phase. The sample-deposition method is simple and robust, as well as flexible and adaptable to a variety of cases. It results in an optimally thin specimen providing low background while maintaining minute amounts of mother liquor around the crystals. The 2 × 2 mm area enables the deposition of up to several microlitres of liquid. Imaging and visualization of the crystals are straightforward on the highly transparent membrane. Thanks to their affordable fabrication, these supports have the potential to become an attractive option for serial experiments at synchrotrons and free-electron lasers.

Retinopatía del prematuro: resultados de un programa de prevención, detección y tratamiento

RESUMEN Introducción: La Retinopatía del Prematuro (ROP) es una de las principales causas de ceguera prevenibles en la infancia. La Fundación Visión implementa; el Programa de Prevención, Detección y Tratamiento en el año 2015. Objetivos: Describir los resultados de implementación y los resultados alcanzados por un programa de ROP en su accesibilidad, efectividad y calidad de atención. Materiales y Métodos: Estudio descriptivo, ambispectivo, de casos consecutivos de recién nacidos prematuros con criterios de evaluación; de una población evaluada en el año 2009 y del 2015 al 2019. Resultados: Las unidades neonatales incluidas aumentaron de 3 a 7; cubriendo Asunción, área Central, Caaguazú y Alto Paraná. De los registros se constato que la cobertura aumento de 36% en el año 2009 a 97% en el 2019. Desde que se instaló el programa; en el primer año la proporción del número de evaluaciones aumento entre el 28 y el 216%; y los resultados globales de julio 2015 a diciembre 2019 fueron: número totales de pacientes con criterio: 2397 pacientes; número totales de pacientes evaluados: 2080 (86,8%), número de pacientes con ROP: 416/2080 pacientes (20%), número de pacientes con ROP que requirieron tratamiento: 76/416 pacientes (18,2%), proporción global de ROP grave con tratamiento: 76/2080 pacientes (3,4%). Conclusiones: El programa a través de un equipo multidisplinario y la inovación con telemedicina logró aumentar la proporción de cobertura y la disminución de los casos graves que requirieron tratamiento.

ABSTRACT Introduction: Retinopathy of Prematurity (ROP) is one of the main preventable causes of blindness in childhood. The Vision Foundation implemented the Prevention, Detection and Treatment Program in 2015. Objective: To describe the implementation results and the outcomes achieved by a ROP program regarding its accessibility, effectiveness and quality of care. Materials and Methods: This was a descriptive and ambispective study of consecutive cases of premature newborns with criteria for evaluation, of a population evaluated in the year 2009 and from 2015 to 2019. Results: The participating neonatal units increased from 3 to 7; covering Asunción, the Central, Caaguazú and Alto Paraná Departments. From the records, it was found that program coverage increased from 36% in 2009 to 97% in 2019. Since the beginning of the program, during the first year the proportion of the number of evaluations increased between 28 and 218%; the global results from July 2015 to December 2019 were: total number of patients with criteria: 2397 patients; total number of patients evaluated: 2,080 (88%), number of patients with ROP: 416/2080 patients (20 %), number of patients with ROP requiring treatment: 76/416 patients (18.3%), overall proportion of severe ROP with treatment: 76/2080 patients (3.4%). Conclusions: The program, using a multidisciplinary team and the innovation of telemedicine, managed to increase the proportion of coverage and the reduction of serious cases that require treatment.

Notch3 Deficiency Attenuates Pulmonary Fibrosis and Impedes Lung-Function Decline.

Fibroblast activation includes differentiation to myofibroblasts and is a key feature of organ fibrosis. The Notch pathway has been involved in myofibroblast differentiation in several tissues, including the lung. Here, we identify a subset of collagen-expressing cells in the lung that exhibit Notch3 activity at homeostasis. After injury, this activation increases, being found in αSMA-expressing myofibroblasts in the mouse and human fibrotic lung. Although previous studies suggest a contribution of Notch3 in stromal activation, in vivo evidence of the role of Notch3 in lung fibrosis remains unknown. In this study, we examine the effects of Notch3 deletion in pulmonary fibrosis and demonstrate that Notch3-deficient lungs are protected from lung injury with significantly reduced collagen deposition after bleomycin administration. The induction of profibrotic genes is reduced in bleomycin-treated Notch3-knockout lungs that consistently present fewer αSMA-positive myofibroblasts. As a result, the volume of healthy lung tissue is higher and lung function is improved in the absence of Notch3. Using in vitro cultures of lung primary fibroblasts, we confirmed that Notch3 participates in their survival and differentiation. Thus, Notch3 deficiency mitigates the development of lung fibrosis because of its role in mediating fibroblast activation. Our findings reveal a previously unidentified mechanism underlying lung fibrogenesis and provide a potential novel therapeutic approach to target pulmonary fibrosis.