American Journal of Physiology. Lung Cellular and Molecular Physiology

Perimenstrual worsening of asthma occurs in up to 40% of asthmatic women, leading to increased acute exacerbations requiring clinical care. The role of sex hormones during these times remains unclear. In the current study, we used a translational approach to determine whether progesterone exacerbates allergic inflammation in the traditional OVA model in BALB/c mice. Simultaneously, we used PBMC from healthy human donors to assess the effects of progesterone on circulating ILC2. Briefly, lungs of ovarectomized (OVX) or sham-operated female (F-Sham) controls were implanted with a progesterone (P4, 25mg) (OVX-P4) or placebo pellet (OVX-Placebo), followed by sensitization and challenge with ovalbumin (OVA)...

Systemic sclerosis (SSc) with interstitial lung disease (SSc-ILD) lacks curative pharmacological treatments, thus necessitating effective animal models for candidate drug discovery. Existing Bleomycin (BLM)-induced SSc-ILD mouse models feature spatially limited pulmonary fibrosis, spontaneously resolving after 28 days. Here, we present an alternative BLM administration approach in female C57BL/6 mice, combining oropharyngeal aspiration (OA) and subcutaneous mini-pump delivery (pump) of BLM to induce a sustained and more persistent fibrosis, while retaining stable skin fibrosis...

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n=22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared to metabolites assayed in matched SSc patients who did not develop PAH (n=22)...

Secreted deoxyribonucleases (DNases), such as DNase-1 and DNase-IL3, degrade extracellular DNA, and endogenous DNases have roles in resolving airway inflammation and guarding against autoimmune responses to nucleotides. Subsets of patients with asthma have high airway DNA levels, but information about DNase activity in health and in asthma is lacking. To characterize DNase activity in health and in asthma, we developed a novel kinetic assay using a Taqman probe sequence that is quickly cleaved by DNase-I to produce a large product signal...

The pathophysiology of pulmonary hypertension (PH) is not fully understood. Here, we tested the hypothesis that hypoxic perfusion of the vasa vasorum of the pulmonary arterial (PA) wall causes PH. Young adult pig lungs were explanted and placed into a modified ex vivo lung perfusion unit (Organ care system, OCS) allowing the separate adjustment of parameters for mechanical ventilation, as well as PA perfusion and bronchial arterial (BA) perfusion. PA vasa vasorum are branches of the BA. The lungs were used either as control (n=3) or intervention group (n=8)...

Chronic exposure to environmental hazards causes airway epithelial dysfunction, primarily impaired physical barriers, immune dysfunction, and repair or regeneration. Impairment of airway epithelial function subsequently leads to exaggerated airway inflammation and remodeling, the main features of chronic obstructive pulmonary disease (COPD). Mitochondrial damage has been identified as one of the mechanisms of airway abnormalities in COPD, which is closely related to airway inflammation and airflow limitation...

Chronic intermittent hypoxia (CIH) is a prevalent condition characterized by recurrent episodes of oxygen deprivation, linked to respiratory and neurological disorders. Prolonged CIH is known to have adverse effects, including endothelial dysfunction, chronic inflammation, oxidative stress, and impaired neuronal function. These factors can contribute to serious comorbidities, including metabolic disorders and cardiovascular diseases. To investigate the molecular impact of CIH, we examined male C57BL/6J mice exposed to CIH for 21 days, comparing to normoxic controls...

BACKGROUND: Respiratory infection, cancer and heart failure can cause abnormal accumulation of fluid in the pleural cavity. The immune responses within the cavity are orchestrated by leucocytes that reside in the serosal associated lymphoid tissue. Natural antibodies (NAbs) are abundant in the serum having a major role in systemic and mucosal immunity, however their occurrence in pleural fluid remains an open question. Our aim herein was to detect and measure the levels of NAbs targeting LPS of M, G, and A class in both, the pleural fluid and the serum of 78 patients with pleural effusions (PEs) of various etiologies...

BACKGROUND: Novel therapies are needed for bronchopulmonary dysplasia (BPD) because no effective treatment exists. Mesenchymal stromal cell extracellular vesicles (MSC-sEVs) have therapeutic efficacy in a mouse pup neonatal hyperoxia BPD model. We tested the hypothesis that MSC-sEVs will improve lung functional and structural development in mechanically ventilated preterm lambs. METHODS: Preterm lambs (~129d; equivalent to human lung development at ~28w gestation) were exposed to antenatal steroids, surfactant, caffeine citrate, and supported by mechanical ventilation for 6-7d...

BACKGROUND: Chronic cigarette smoke exposure decreases lung expression of WWOX which is known to protect the endothelial barrier during infectious models of ARDS. METHODS: Proteomic analysis of WWOX -silenced endothelial cells (ECs) was done using tandem mass tag mass spectrometry (TMT-MS). WWOX -silenced ECs as well as those isolated from endothelial Wwox knockout (EC Wwox KO) mice were subjected to cyclic stretch (18% elongation, 0.5 Hz, 4 hours). Cellular lysates and media supernatant were harvested for assays of cellular signaling, protein expression, and cytokine release...

Alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD) orchestrate persistent inflammation in the airway. However, sub-populations of AMs participating in the chronic inflammation have been poorly characterized. We previously reported that Siglec-1 expression on AMs, which is important for bacteria engulfment, was decreased in COPD. Here, we show that Siglec-1-negative AMs isolated from COPD lung tissues exhibit a pro-inflammatory phenotype and is associated with poor clinical outcomes in patients with COPD...

Airway smooth muscle cell (ASM) is renowned for its involvement in airway hyperresponsiveness through impaired ASM relaxation and bronchoconstriction in asthma which poses a significant challenge in the field. Recent studies have explored different targets in ASM to alleviate airway hyperresponsiveness, however, a sizeable portion of asthmatics still experience poor control. In our study, we explored protein phosphatase 2A (PP2A) in ASM as it has been reported to regulate cellular contractility by controlling intracellular calcium ([Ca2+ ]i ), ion channels, and respective regulatory proteins...

Novel screening techniques for early detection of lung cancer are urgently needed. Profiling circulating tumor cell-free DNA (ctDNA) has emerged as a promising tool for biopsy-free tumor genotyping. However, both the scarcity and short half-life of ctDNA substantially limit the sensitivity and clinical utility of ctDNA detection methodologies. Our discovery that Red Blood Cells (RBCs) sequester mitochondrial DNA opens a new avenue for detecting circulating nucleic acids, as RBCs represent an unrecognized reservoir of circulating nucleic acid...

We have reported previously that during hypoxia exposure, the expression of mature miR-17~92 was first upregulated and then downregulated in pulmonary artery smooth muscle cells (PASMC) and in mouse lungs in vitro and in vivo . Here we investigated the mechanisms regulating this bi-phasic expression of miR-17~92 in PASMC in hypoxia. We measured the level of primary miR-17~92 in PASMC during hypoxia exposure and found that short-term hypoxia exposure (3%O2 , 6 hours) induced the level of primary miR-17~92, while long-term hypoxia exposure (3%O2 , 24 hours) decreased its level, suggesting a bi-phasic regulation of miR-17~92 expression at the transcriptional level...

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Acute respiratory distress syndrome (ARDS) is a fatal pulmonary disorder characterized by severe hypoxia and inflammation. Systemic and pulmonary infections are a leading cause of ARDS. The common respiratory pathogens include bacteria and virus, including Pseudomonas aeruginosa, Streptococcus aureus, Enterobacter species, coronavirus, influenza, and herpesviruses. COVID-19-associated ARDS is a new etiologic phenotype of the disease. The pathogenesis of ARDS caused by bacteria and viruses differs in host immune responses and lung mesenchymal injury...

Extracellular vesicle (EV) biology in neonatal lung development and disease is a rapidly growing area of investigation. While EV research in the neonatal population lags behind EV research in adult lung diseases, recent discoveries demonstrate promise in furthering our understanding of the pathophysiology of bronchopulmonary dysplasia and the potential use of EVs in the clinical setting, as both biomarkers and therapeutic agents. This mini-review article explores some of the recent advances in this field and our evolving knowledge of the role of EVs in bronchopulmonary dysplasia...

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signalling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined...

Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation and increased permeability of lung microvascular cells. CD26/Dipeptidyl peptidase-4 (DPP4) is a type II membrane protein that is expressed in several cell types and mediates multiple pleiotropic effects. We previously reported that DPP4 inhibition by sitagliptin attenuates lipopolysaccharide (LPS)-induced lung injury in mice. The current study characterized the functional role of CD26/DPP4 expression in LPS-induced lung injury in mice, isolated alveolar macrophages, and cultured lung endothelial cells...