-
Respiratory Medicine Oct 2023Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD)....
BACKGROUND
Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that FMI and FFMI have different impacts on 1) emphysema and 2) pulmonary function and health-related quality of life of COPD patients.
METHODS
Patients with COPD (n = 228), enrolled in a multicenter prospective 3-year cohort were classified into four groups based on baseline median FMI and FFMI values. Emphysema assessed as the ratio of low attenuation area to total lung volume (LAA%) on computed tomography, pulmonary function, and health-related quality of life assessed using the St. George's Respiratory Questionnaire (SGRQ) were compared.
RESULTS
The four groups had statistically significant differences in LAA%, pulmonary function, and SGRQ scores. The Low FMI Low FFMI group exhibited the highest LAA%, lowest pulmonary function, and worst SGRQ scores among the four groups. In addition, these differences were consistent over 3 years. Multivariate analysis showed that low FMI was associated with high LAA%, low inspiratory capacity/total lung capacity (IC/TLC), and carbon monoxide transfer coefficient (K). In contrast, low FFMI was associated with these factors as well as worse SGRQ scores.
CONCLUSION
FMI and FFMI have different effects on the clinical manifestations of COPD. Both low fat and muscle mass contributed to severe emphysema, whereas only low muscle mass contributed to worse health-related quality of life in patients with COPD.
Topics: Humans; Prospective Studies; Quality of Life; Pulmonary Disease, Chronic Obstructive; Lung; Pulmonary Emphysema; Emphysema; Body Mass Index; Body Composition
PubMed: 37390978
DOI: 10.1016/j.rmed.2023.107346 -
LncRNA SLCO4A1-AS1 suppresses lung cancer progression by sequestering the TOX4-NTSR1 signaling axis.Journal of Biomedical Science Sep 2023Metastasis is a multistep process involving the migration and invasion of cancer cells and is a hallmark of cancer malignancy. Long non-coding RNAs (lncRNAs) play...
BACKGROUND
Metastasis is a multistep process involving the migration and invasion of cancer cells and is a hallmark of cancer malignancy. Long non-coding RNAs (lncRNAs) play critical roles in the regulation of metastasis. This study aims to elucidate the role of the lncRNA solute carrier organic anion transporter family member 4A1-antisense 1 (SLCO4A1-AS1) in metastasis and its underlying regulatory mechanisms.
METHODS
A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify metastasis-associated lncRNAs. Transwell migration and invasion assays, and a tail vein-injection mouse model were used to assess the migration and invasion of cancer cells in vitro and in vivo, respectively. High-throughput screening methods, including MASS Spectrometry and RNA sequencing (RNA-seq), were used to identify the downstream targets of SLCO4A1-AS1. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, RNA pull-down, RNA immunoprecipitation (RIP), fluorescence in situ hybridization (FISH), and chromatin immunoprecipitation (ChIp) assays were conducted to identify and validate the underlying regulatory mechanisms of SLCO4A1-AS1.
RESULTS
SLCO4A1-AS1 reduced cancer cell migration and invasion by disrupting cytoskeleton filaments, and was associated with longer overall survival in patients with lung adenocarcinoma. SLCO4A1-AS1 directly interacted with the DNA-binding protein, TOX High Mobility Group Box Family Member 4 (TOX4), to inhibit TOX4-induced migration and invasion. Furthermore, RNA-seq revealed that neurotensin receptor 1 (NTSR1) is a novel and convergent downstream target of SLCO4A1-AS1 and TOX4. Mechanistically, SLCO4A1-AS1 functions as a decoy of TOX4 by interrupting its interaction with the NTSR1 promoter and preventing NTSR1 transcription. Functionally, NTSR1 promotes cancer cell migration and invasion through cytoskeletal remodeling, and knockdown of NTSR1 significantly inhibits TOX4-induced migration and invasion.
CONCLUSION
These findings demonstrated that SLCO4A1-AS1 antagonizes TOX4/NTSR1 signaling, underscoring its pivotal role in lung cancer cell migration and invasion. These findings hold promise for the development of novel therapeutic strategies targeting the SLCO4A1-AS1/TOX4/NTSR1 axis as a potential avenue for effective therapeutic intervention in lung cancer.
Topics: Animals; Mice; RNA, Long Noncoding; In Situ Hybridization, Fluorescence; Lung Neoplasms; Signal Transduction; Lung
PubMed: 37726723
DOI: 10.1186/s12929-023-00973-9 -
Thoracic Surgery Clinics Nov 2023Lung cancer screening has been shown to reduce lung cancer mortality and is recommended for individuals meeting age and smoking history criteria. Despite the expansion... (Review)
Review
Lung cancer screening has been shown to reduce lung cancer mortality and is recommended for individuals meeting age and smoking history criteria. Despite the expansion of lung cancer screening guidelines in 2021, racial/ethnic and sex disparities persist. High-risk racial minorities and women are more likely to be diagnosed with lung cancer at younger ages and have lower smoking histories when compared with White and male counterparts, resulting in higher rates of ineligibility for screening. Risk prediction models, biomarkers, and deep learning may help refine the selection of individuals who would benefit from screening.
Topics: Humans; Male; Female; Lung Neoplasms; Smoking; Early Detection of Cancer; Lung; Mass Screening
PubMed: 37806735
DOI: 10.1016/j.thorsurg.2023.04.002 -
The Journal of Pharmacology and... Jan 2024Inhaled toxicants are used for diverse purposes, ranging from industrial applications such as agriculture, sanitation, and fumigation to crowd control and chemical... (Review)
Review
Inhaled toxicants are used for diverse purposes, ranging from industrial applications such as agriculture, sanitation, and fumigation to crowd control and chemical warfare, and acute exposure can induce lasting respiratory complications. The intentional release of chemical warfare agents (CWAs) during World War I caused life-long damage for survivors, and CWA use is outlawed by international treaties. However, in the past two decades, chemical warfare use has surged in the Middle East and Eastern Europe, with a shift toward lung toxicants. The potential use of industrial and agricultural chemicals in rogue activities is a major concern as they are often stored and transported near populated areas, where intentional or accidental release can cause severe injuries and fatalities. Despite laws and regulatory agencies that regulate use, storage, transport, emissions, and disposal, inhalational exposures continue to cause lasting lung injury. Industrial irritants (e.g., ammonia) aggravate the upper respiratory tract, causing pneumonitis, bronchoconstriction, and dyspnea. Irritant gases (e.g., acrolein, chloropicrin) affect epithelial barrier integrity and cause tissue damage through reactive intermediates or by direct adduction of cysteine-rich proteins. Symptoms of CWAs (e.g., chlorine gas, phosgene, sulfur mustard) progress from airway obstruction and pulmonary edema to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which results in respiratory depression days later. Emergency treatment is limited to supportive care using bronchodilators to control airway constriction and rescue with mechanical ventilation to improve gas exchange. Complications from acute exposure can promote obstructive lung disease and/or pulmonary fibrosis, which require long-term clinical care. SIGNIFICANCE STATEMENT: Inhaled chemical threats are of growing concern in both civilian and military settings, and there is an increased need to reduce acute lung injury and delayed clinical complications from exposures. This minireview highlights our current understanding of acute toxicity and pathophysiology of a select number of chemicals of concern. It discusses potential early-stage therapeutic development as well as challenges in developing countermeasures applicable for administration in mass casualty situations.
Topics: Humans; Lung; Chlorine; Chemical Warfare Agents; Phosgene; Acute Lung Injury; Irritants
PubMed: 37863486
DOI: 10.1124/jpet.123.001822 -
American Journal of Physiology. Lung... Sep 2023There are no effective targeted therapies to treat acute respiratory distress syndrome (ARDS). Recently, the commonly used diabetes and obesity medications,...
There are no effective targeted therapies to treat acute respiratory distress syndrome (ARDS). Recently, the commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have been found to have anti-inflammatory properties. We, therefore, hypothesized that liraglutide pretreatment would attenuate murine sepsis-induced acute lung injury (ALI). We used a two-hit model of ALI (sepsis+hyperoxia). Sepsis was induced by intraperitoneal injection of cecal slurry (CS; 2.4 mg/g) or 5% dextrose (control) followed by hyperoxia [HO; fraction of inspired oxygen ([Formula: see text]) = 0.95] or room air (control; [Formula: see text] = 0.21). Mice were pretreated twice daily with subcutaneous injections of liraglutide (0.1 mg/kg) or saline for 3 days before initiation of CS+HO. At 24-h post CS+HO, physiological dysfunction was measured by weight loss, severity of illness score, and survival. Animals were euthanized, and bronchoalveolar lavage (BAL) fluid, lung, and spleen tissues were collected. Bacterial burden was assessed in the lung and spleen. Lung inflammation was assessed by BAL inflammatory cell numbers, cytokine concentrations, lung tissue myeloperoxidase activity, and cytokine expression. Disruption of the alveolar-capillary barrier was measured by lung wet-to-dry weight ratios, BAL protein, and epithelial injury markers (receptor for advanced glycation end products and sulfated glycosaminoglycans). Histological evidence of lung injury was quantified using a five-point score with four parameters: inflammation, edema, septal thickening, and red blood cells (RBCs) in the alveolar space. Compared with saline treatment, liraglutide improved sepsis-induced physiological dysfunction and reduced lung inflammation, alveolar-capillary barrier disruption, and lung injury. GLP-1 receptor activation may hold promise as a novel treatment strategy for sepsis-induced ARDS. Additional studies are needed to better elucidate its mechanism of action. In this study, pretreatment with liraglutide, a commonly used diabetes medication and glucagon-like peptide-1 (GLP-1) receptor agonist, attenuated sepsis-induced acute lung injury in a two-hit mouse model (sepsis + hyperoxia). Septic mice who received the drug were less sick, lived longer, and displayed reduced lung inflammation, edema, and injury. These therapeutic effects were not dependent on weight loss. GLP-1 receptor activation may hold promise as a new treatment strategy for sepsis-induced acute respiratory distress syndrome.
Topics: Animals; Mice; Liraglutide; Hyperoxia; Glucagon-Like Peptide-1 Receptor; Acute Lung Injury; Lung; Cytokines; Glucagon-Like Peptide 1; Respiratory Distress Syndrome; Sepsis; Edema
PubMed: 37489855
DOI: 10.1152/ajplung.00041.2023 -
Cell May 2024SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic...
SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.
Topics: Humans; SARS-CoV-2; Killer Cells, Natural; NK Cell Lectin-Like Receptor Subfamily K; COVID-19; Immune Evasion; Histocompatibility Antigens Class I; Animals; Cytotoxicity, Immunologic; Down-Regulation; Lung
PubMed: 38653235
DOI: 10.1016/j.cell.2024.03.026 -
Nature Communications May 2024SARS-CoV-2 infection causes severe pulmonary manifestations, with poorly understood mechanisms and limited treatment options. Hyperferritinemia and disrupted lung iron...
SARS-CoV-2 infection causes severe pulmonary manifestations, with poorly understood mechanisms and limited treatment options. Hyperferritinemia and disrupted lung iron homeostasis in COVID-19 patients imply that ferroptosis, an iron-dependent cell death, may occur. Immunostaining and lipidomic analysis in COVID-19 lung autopsies reveal increases in ferroptosis markers, including transferrin receptor 1 and malondialdehyde accumulation in fatal cases. COVID-19 lungs display dysregulation of lipids involved in metabolism and ferroptosis. We find increased ferritin light chain associated with severe COVID-19 lung pathology. Iron overload promotes ferroptosis in both primary cells and cancerous lung epithelial cells. In addition, ferroptosis markers strongly correlate with lung injury severity in a COVID-19 lung disease model using male Syrian hamsters. These results reveal a role for ferroptosis in COVID-19 pulmonary disease; pharmacological ferroptosis inhibition may serve as an adjuvant therapy to prevent lung damage during SARS-CoV-2 infection.
Topics: Ferroptosis; COVID-19; Animals; Humans; Male; Lung; SARS-CoV-2; Mesocricetus; Female; Iron; Middle Aged; Disease Models, Animal; Aged; Lung Injury; Iron Overload; Adult; Cricetinae
PubMed: 38769293
DOI: 10.1038/s41467-024-48055-0 -
American Journal of Physiology. Lung... Sep 2023Obesity is mostly associated with adverse health consequences, but may also elicit favorable effects under chronic conditions. This "obesity paradox" is under debate for...
Obesity is mostly associated with adverse health consequences, but may also elicit favorable effects under chronic conditions. This "obesity paradox" is under debate for pulmonary diseases. As confounding factors complicate conclusions from human studies, this study used a controlled animal model combining diet-induced obesity and chronic hypoxia as a model for pulmonary hypertension and chronic obstructive pulmonary disease. Male C57BL/6 mice were fed control or high-fat diet for 30 wk, and half of the animals were exposed to chronic hypoxia (13% O) for 3 wk. Hypoxia induced right ventricular hypertrophy, thickening of pulmonary arterial and capillary walls, higher lung volumes, and increased hemoglobin concentrations irrespective of the body weight. In contrast, lung proteomes differed substantially between lean- and obese-hypoxic mice. Many of the observed changes were linked to vascular and extracellular matrix (ECM) proteins. In lean-hypoxic animals, circulating platelets were reduced and abundances of various clotting-related proteins were altered, indicating a hypercoagulable phenotype. Moreover, the septal ECM composition was changed, and airspaces were significantly distended pointing to lung hyperinflation. These differences were mostly absent in the obese-hypoxic group. However, the obesity-hypoxia combination induced the lowest blood CO concentrations, indicating hyperventilation for sufficient oxygen supply. Moreover, endothelial surface areas were increased in obese-hypoxic mice. Thus, obesity exerts differential effects on lung adaptation to hypoxia, which paradoxically include not only adverse but also rather protective changes. These differences have a molecular basis in the lung proteome and may influence the pathogenesis of lung diseases. This should be taken into account for future individualized prevention and therapy. An "obesity paradox" is discussed for pulmonary diseases. By linking lung proteome analyses to pulmonary structure and function, we demonstrate that diet-induced obesity affects lung adaptation to chronic hypoxia in various ways. The observed changes include not only adverse but also protective effects and are associated with altered abundances of vascular and extracellular matrix proteins. These results highlight the existence of relevant differences in individuals with obesity that may influence the pathogenesis of lung diseases.
Topics: Humans; Mice; Animals; Male; Proteome; Mice, Inbred C57BL; Lung; Obesity; Hypertension, Pulmonary; Hypoxia
PubMed: 37461840
DOI: 10.1152/ajplung.00125.2023 -
Proceedings of the National Academy of... Nov 2023COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with...
COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. Growth hormone-releasing hormone receptor (GHRH-R) is expressed in the lung and heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses to bleomycin lung injury and inflammation in granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced pulmonary dysfunction and heart injury in a BSL-2 mouse model. Male and female K18-htg mice were inoculated with SARS-CoV-2/USA-WA1/2020, BSL-2-compliant recombinant VSV-eGFP-SARS-CoV-2-Spike (rVSV-SARS-CoV-2), or PBS, and lung viral load, weight loss, histopathology, and gene expression were compared. K18-htg mice infected with rVSV-SARS-CoV-2 were treated daily with subcutaneous MIA-602 or vehicle and conscious, unrestrained plethysmography performed on days 0, 3, and 5 (n = 7 to 8). Five days after infection mice were killed, and blood and tissues collected for histopathology and protein/gene expression. Both native SARS-CoV-2 and rVSV-SARS-CoV-2 presented similar patterns of weight loss, infectivity (~60%), and histopathologic changes. Daily treatment with MIA-602 conferred weight recovery, reduced lung perivascular inflammation/pneumonia, and decreased lung/heart ICAM-1 expression compared to vehicle. MIA-602 rescued altered respiratory rate, increased expiratory parameters (Te, PEF, EEP), and normalized airflow parameters (Penh and Rpef) compared to vehicle, consistent with decreased airway inflammation. RNASeq followed by protein analysis revealed heightened levels of inflammation and end-stage necroptosis markers, including ZBP1 and pMLKL induced by rVSV-SARS-CoV-2, that were normalized by MIA-602 treatment, consistent with an anti-inflammatory and pro-survival mechanism of action in this preclinical model of COVID-19 pneumonia.
Topics: Mice; Male; Female; Animals; SARS-CoV-2; COVID-19; Lung; Inflammation; Respiratory Distress Syndrome; Weight Loss; Mice, Transgenic; Disease Models, Animal
PubMed: 37983492
DOI: 10.1073/pnas.2308342120 -
PLoS Pathogens Jul 2023Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals....
Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures ("tolerant"), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah-/- AMs were less responsive to LPS stimulation and less phagocytic than were Aoah+/+ AMs. Upon innate stimulation in the airways, Aoah-/- mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah-/- mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized ("tolerized") AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah-/- AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah-/- AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung.
Topics: Animals; Mice; Lipopolysaccharides; Lung; Macrophages, Alveolar; Toll-Like Receptor 4; Carboxylic Ester Hydrolases
PubMed: 37498977
DOI: 10.1371/journal.ppat.1011556