Cancer Immunol Immunother
January 2025
Background: Checkpoint inhibitor pneumonitis (CIP) that develops following immune checkpoint inhibitor (ICI) treatment can be difficult to distinguish from other common etiologies of lung inflammation in cancer patients. Here, we evaluate the bronchoalveolar lavage fluid (BAL) for potential biomarkers specific to CIP.
Methods: We conducted a retrospective study of patients who underwent standard of care bronchoscopy to compare the cytokines of interest between patients with and without CIP and with and without immune-mediated pulmonary diseases.
Ozone (O ) inhalation triggers asthmatic airway hyperresponsiveness (AHR), but the mechanisms by which this occurs are unknown. Previously, we developed a murine model of dust mite, ragweed, and (DRA)-induced allergic lung inflammation followed by O exposure for mechanistic investigation. The present study used single cell RNA-sequencing for unbiased profiling of immune cells within the lungs of mice exposed to DRA, O , or DRA+O , to identify the components of the immune cell niche that contribute to AHR.
View Article and Find Full Text PDFIntroduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes.
View Article and Find Full Text PDFCOVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the β-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood.
View Article and Find Full Text PDFBackground: The SARS CoV-2 pandemic has resulted in more than 1.1 million deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited.
View Article and Find Full Text PDFThe lung is a dynamic mechanical organ and several pulmonary disorders are characterized by heterogeneous changes in the lung's local mechanical properties (i.e. stiffness).
View Article and Find Full Text PDFThe pro-inflammatory response of alveolar macrophages to injurious physical forces during mechanical ventilation is regulated by the anti-inflammatory microRNA, miR-146a. Increasing miR-146a expression to supraphysiologic levels using untargeted lipid nanoparticles reduces ventilator-induced lung injury but requires a high initial dose of miR-146a making it less clinically applicable. In this study, we developed mannosylated lipid nanoparticles that can effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a.
View Article and Find Full Text PDFUncertainty persists whether anaerobic bacteria represent important pathogens in aspiration pneumonia. In a nested case-control study of mechanically ventilated patients classified as macro-aspiration pneumonia (MAsP, n = 56), non-macro-aspiration pneumonia (NonMAsP, n = 91), and uninfected controls (n = 11), we profiled upper (URT) and lower respiratory tract (LRT) microbiota with bacterial 16S rRNA gene sequencing, measured plasma host-response biomarkers, analyzed bacterial communities by diversity and oxygen requirements, and performed unsupervised clustering with Dirichlet Multinomial Models (DMM). MAsP and NonMAsP patients had indistinguishable microbiota profiles by alpha diversity and oxygen requirements with similar host-response profiles and 60-day survival.
View Article and Find Full Text PDFAcute respiratory distress syndrome (ARDS) represents a significant burden to the healthcare system, with ≈200 000 cases diagnosed annually in the USA. ARDS patients suffer from severe refractory hypoxemia, alveolar-capillary barrier dysfunction, impaired surfactant function, and abnormal upregulation of inflammatory pathways that lead to intensive care unit admission, prolonged hospitalization, and increased disability-adjusted life years. Currently, there is no cure or FDA-approved therapy for ARDS.
View Article and Find Full Text PDFThe pro-inflammatory response of alveolar macrophages to injurious physical forces during mechanical ventilation is regulated by the anti-inflammatory microRNA, miR-146a. Increasing miR-146a expression to supraphysiologic levels using untargeted lipid nanoparticles reduces ventilator-induced lung injury, but requires a high initial dose of miR-146a making it less clinically applicable. In this study, we developed mannosylated lipid nanoparticles that can effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a.
View Article and Find Full Text PDFThe acute respiratory distress syndrome (ARDS) is a life-threatening condition that causes respiratory failure. Despite numerous clinical trials, there are no molecularly targeted pharmacologic therapies to prevent or treat ARDS. Drug delivery during ARDS is challenging due to the heterogenous nature of lung injury and occlusion of lung units by edema fluid and inflammation.
View Article and Find Full Text PDFToxicol Appl Pharmacol
January 2023
Asthma is a chronic inflammatory airway disease characterized by acute exacerbations triggered by inhaled allergens, respiratory infections, or air pollution. Ozone (O), a major component of air pollution, can damage the lung epithelium in healthy individuals. Despite this association, little is known about the effects of O and its impact on chronic lung disease.
View Article and Find Full Text PDFAsthma is phenotypically heterogeneous with several distinctive pathological mechanistic pathways. Previous studies indicate that neutrophilic asthma has a poor response to standard asthma treatments comprising inhaled corticosteroids. Therefore, it is important to identify critical factors that contribute to increased numbers of neutrophils in asthma patients whose symptoms are poorly controlled by conventional therapy.
View Article and Find Full Text PDFUnlabelled: Determine the role of surfactant protein D (SPD) in sepsis.
Design: Murine in vivo study.
Setting: Research laboratory at an academic medical center.
Severe asthma is characterized by steroid insensitivity and poor symptom control and is responsible for most asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding of mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in human asthmatic lungs.
View Article and Find Full Text PDFAdvancements in methods, technology, and our understanding of the pathobiology of lung injury have created the need to update the definition of experimental acute lung injury (ALI). We queried 50 participants with expertise in ALI and acute respiratory distress syndrome using a Delphi method composed of a series of electronic surveys and a virtual workshop. We propose that ALI presents as a "multidimensional entity" characterized by four "domains" that reflect the key pathophysiologic features and underlying biology of human acute respiratory distress syndrome.
View Article and Find Full Text PDFThe acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function.
View Article and Find Full Text PDFBackground: Acute Respiratory Distress Syndrome (ARDS) is a frequent cause of respiratory failure in intensive care unit (ICU) patients and results in significant morbidity and mortality. ARDS often develops as a result of a local or systemic inflammatory insult. Cancer can lead to systemic inflammation but whether cancer is an independent risk factor for developing ARDS is unknown.
View Article and Find Full Text PDFAm J Physiol Lung Cell Mol Physiol
May 2021
Mechanical ventilation generates injurious forces that exacerbate lung injury. These forces disrupt lung barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides including microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation.
View Article and Find Full Text PDFPulmonary macrophages play a critical role in the recognition of pathogens, initiation of host defense via inflammation, clearance of pathogens from the airways, and resolution of inflammation. Recently, we have shown a pivotal role for the nuclear factor of activated T-cell cytoplasmic member 3 (NFATc3) transcription factor in modulating pulmonary macrophage function in LPS-induced acute lung injury (ALI) pathogenesis. Although the NFATc proteins are activated primarily by calcineurin-dependent dephosphorylation, here we show that LPS induces posttranslational modification of NFATc3 by polyADP-ribose polymerase 1 (PARP-1)-mediated polyADP-ribosylation.
View Article and Find Full Text PDFEx vivo lung perfusion (EVLP) is increasingly used to treat and assess lungs before transplant. Minimizing ventilator induced lung injury (VILI) during EVLP is an important clinical need, and negative pressure ventilation (NPV) may reduce VILI compared with conventional positive pressure ventilation (PPV). However, it is not clear if NPV is intrinsically lung protective or if differences in respiratory pressure-flow waveforms are responsible for reduced VILI during NPV.
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