American Journal of Physiology. Lung Cellular and Molecular Physiology

Mucopolysaccharidosis type IIIA (MPS IIIA) is characterised by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulphamidase, and the subsequent primary accumulation of undegraded heparan sulphate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice...

Post-natal lung development results in an increasingly functional organ prepared for gas exchange and pathogenic challenges. It is achieved through cellular differentiation and migration. Changes in the tissue architecture during this development process are well documented and increasing cellular diversity associated with it are reported in recent years. Despite recent progress, transcriptomic and molecular pathways associated with human post-natal lung development are yet to be fully understood. In this study we investigated gene expression patterns associated with healthy pediatric lung development in four major enriched cell populations (epithelial, endothelial, and non-endothelial mesenchymal cells, along with lung leukocytes) from one-day-old to eight-year-old organ donors with no known lung disease...

Although tobramycin increases lung function in people with cystic fibrosis (pwCF), the density of Pseudomonas aeruginosa (P. aeruginosa) in the lungs is only modestly reduced by tobramycin; hence, the mechanism whereby tobramycin improves lung function is not completely understood. Here, we demonstrate that tobramycin increases 5' tRNA-fMet halves in outer membrane vesicles (OMVs) secreted by laboratory and CF clinical isolates of P. aeruginosa . The 5' tRNA-fMet halves are transferred from OMVs into primary CF human bronchial epithelial cells (CF-HBEC), decreasing OMV-induced IL-8 and IP-10 secretion...

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than non-deployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the subjects in this cohort reported exposure to sulfur dioxide (SO2 ), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease...

Pulmonary hypertension (PH) is a condition in which remodeling of the pulmonary vasculature leads to hypertrophy of the muscular vascular wall and extension of muscle into non-muscular arteries. These pathologic changes are predominantly due to abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), enhanced cellular functions that have been linked to increases in the cell membrane protein aquaporin-1 (AQP1). However, the mechanisms underlying increased AQP1 abundance have not been fully elucidated...

Excessive or persistent inflammation may have detrimental effects on lung structure and function. Currently, our understanding of conserved host mechanisms that control the inflammatory response remains incompletely understood. In this study, we investigated the role of type I interferon signaling in the inflammatory response against diverse clinically relevant stimuli. Using mice deficient in type I interferon signaling (IFNAR1-/-), we demonstrate that the absence of interferon signaling resulted in a robust and persistent inflammatory response against Pseudomonas aeruginosa , lipopolysaccharide, and chemotherapeutic agent bleomycin...

Pulmonary function testing (PFT) in mice includes biomechanical assessment of lung function relevant to physiology in health and its alteration in disease, hence, it is frequently used in preclinical modeling of human lung pathologies. Despite numerous reports of PFT in mice of various ages, there is a lack of reference data for developing mice collected using consistent methods. Therefore, we profiled PFTs in male and female C57BL/6J mice from 2 to 23 weeks of age, providing reference values for age- and sex-dependent changes in mouse lung biomechanics during development and young adulthood...

Lung surfactant collectins, surfactant protein A (SP-A) and D (SP-D), are oligomeric C-type lectins involved in lung immunity. Through their carbohydrate recognition domain, they recognize carbohydrates at pathogen surfaces and initiate lung innate immune response. Here, we propose that they may also be able to bind to other carbohydrates present in typical cell surfaces, such as the alveolar epithelial glycocalyx. To test this hypothesis, we analyzed and quantified the binding affinity of SP-A and SP-D to different sugars and glycosaminoglycans (GAGs) by microscale thermophoresis (MST)...

Cold stored platelets (CS) are once again being reintroduced for clinical use. Transfused CS offer benefits over room temperature stored platelets (RTS) such as increased hemostatic effects and prolongation of shelf-life. Despite these advantages little is known about their association with transfusion-related acute lung injury (TRALI). TRALI is associated with prolonged storage RTS and has a mortality of > 15%. Determining the safety of CS is important considering their proposed use in TRALI-vulnerable populations with systemic inflammation such as surgical or trauma patients...

During the progression of pleural fibrosis, pleural mesothelial cells (PMCs) undergo a phenotype switching process known as mesothelial-mesenchymal transition (MesoMT). During MesoMT, transformed PMCs become myofibroblasts which produce increased extracellular matrix (ECM) proteins, including collagen and fibronectin (FN1) that is critical to develop fibrosis. Here, we studied the mechanism that regulates FN1 expression in myofibroblasts derived from HPMCs. We found that myocardin (Myocd), a transcriptional coactivator of serum response factor (SRF) and a master regulator of smooth muscle and cardiac muscle differentiation, strongly controls HPMC FN1 gene expression...

Alveolar type I (ATI) cells cover >95% of the lung's distal surface and facilitate gas exchange through their exceptionally thin shape. ATI cells in vivo are replenished by alveolar type II cell division and differentiation, but a detailed understanding of ATI biology has been hampered by the challenges in direct isolation of these cell due to their fragility, and incomplete understanding of the signaling interactions that promote differentiation of ATII to ATI cells. Here we explored the signals that maintain ATII versus promote ATI fates in 3D organoid cultures, and developed a human alveolar type I differentiation medium (hATIDM) suitable for generating ATI cells from either mixed distal human lung cells or purified ATII cells...

Prolonged labor can lead to infection, fetal distress, asphyxia, and life-threatening harm to both the mother and baby. Surfactant Protein A (SP-A) was shown to contribute to maintenance of pregnancy and timing of term labor. SP-A modulates the stoichiometric expression of the SP-R210L and SP-R210S isoforms of the SP-R210 receptor on alveolar macrophages (AMs). Lack of SP-R210L dysregulates macrophage inflammatory responses. We asked whether SP-A alters normal and inflammation-induced parturition through SP-R210 using SP-A- and SP-R210L -deficient mice...

It is unclear what effect biological sex has on the outcomes of acute lung injury (ALI). Clinical studies are confounded by their observational design. We addressed this knowledge gap with a preclinical systematic review of ALI animal studies. We searched MEDLINE and Embase for studies of intratracheal/intranasal/aerosolized lipopolysaccharide (LPS) administration, the most common ALI model, and reported sex-stratified data. Screening and data extraction were conducted in duplicate. Our primary outcome was histological tissue injury and secondary outcomes included alveolar-capillary barrier alterations and inflammatory markers...

Chronic obstructive pulmonary disease (COPD) is caused by cigarette smoke (CS) exposure but can be often progressive even in former smokers. Exposure of mice to CS for 22 weeks causes emphysema, but whether emphysema persists after cessation of CS exposure is not clear. The purpose of this study was to determine whether emphysema persists in mice following a recovery period of 22 wks and whether a susceptibility factor, such as deficiency in the Bcl-2-interacting killer (Bik), is required for this persistence...

This study addressed the efficacy of a liposome-encapsulated 9 amino acid peptide (PIP-2) for the prevention or treatment of acute lung injury (ALI) +/- sepsis. PIP-2 inhibits the PLA2 activity of peroxiredoxin 6, thereby preventing Rac release and activation of NADPH oxidases, types 1 and 2. Female Yorkshire pigs were infused intravenously with lipopolysaccharide (LPS) + liposomes (untreated) or LPS + PIP-2 encapsulated in liposomes (treated). Pigs were mechanically ventilated and continuously monitored; they were euthanized after 8 hours or earlier if pre-established humane endpoints were reached...

The utility of cell free (cf) DNA has extended as a surrogate or clinical biomarker for various diseases. However, a more profound and expanded understanding of the diverse cfDNA population and its correlation with physiological phenotypes and environmental factors is imperative for utilizing its full potential. The high altitude (HA; altitude >2500 m above sea level) environment characterized by hypobaric hypoxia offers an observational case-control design to study the differential cfDNA profile in high-altitude pulmonary edema (HAPE) patients (n=112) and healthy HA sojourners (n=111)...

Chlorine gas (Cl2 ) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. Modeling the human etiology of Cl2 -induced acute lung injury (ALI), forensic biomarkers, and targeted countermeasures development have been hampered by inadequate large animal models. The objective of this study was to develop a translational model of Cl2 -induced ALI in swine to understand toxico-pathophysiology and is suitable for screening potential medical countermeasures, and identify biomarkers useful for forensic analysis...

INTRODUCTION: Nasal NO (nNO) is low in most Primary Ciliary Dyskinesia (PCD) patients. Decreased ciliary motion could lead to antigen stasis, increasing oxidant production; and NO oxidation in the airways could both decrease gas phase NO and increase nitrosative stress. MATERIALS AND METHODS: We studied primary airway epithelial cells from healthy controls (HC) and PCD patients with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to fluorescently- labeled antigen Dermatophagoiedes pteronyssinus (Derp1-f)...

Sphingosine kinase 1 (SPHK1) has been shown to play a key role in the pathogenesis of asthma where SPHK1 generated S1P is known to mediate innate and adaptive immunity while promoting mast cell degranulation. Goblet cell metaplasia (GCM) contributes to airway obstruction in asthma and has been demonstrated in animal models. We investigated the role of PF543, a SPHK1 specific inhibitor, in preventing the pathogenesis of GCM using a murine (C57BL/6) model of allergen-induced acute asthma. Treatment with PF543 prior to triple allergen exposure (DRA: House dust mite, Ragweed pollen and Aspergillus) reduced inflammation, eosinophilic response, and GCM followed by reduced airway hyperreactivity to intravenous methacholine...

Early-life respiratory virus infections have been correlated with enhanced development of childhood asthma. In particular, significant numbers of RSV-hospitalized infants go on to develop lung disease. It has been suggested that early-life viral infections may lead to altered lung development or repair that negatively impacts lung function later in life. Our data demonstrate that early-life RSV infection modifies lung structure, leading to decreased lung function. At 5 weeks post-neonatal RSV infection, significant defects are observed in baseline pulmonary function test (PFT) parameters consistent with decreased lung function as well as enlarged alveolar spaces...