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The Journal of Allergy and Clinical... Jul 2021In this narrative review, we summarize the literature and provide updates on recent studies of air pollution exposures and child lung function and lung function growth.... (Review)
Review
In this narrative review, we summarize the literature and provide updates on recent studies of air pollution exposures and child lung function and lung function growth. We include exposures to outdoor air pollutants that are monitored and regulated through air quality standards, and air pollutants that are not routinely monitored or directly regulated, including wildfires, indoor biomass and coal burning, gas and wood stove use, and volatile organic compounds. Included is a more systematic review of the recent literature on long-term air pollution and child lung function because this is an indicator of future adult respiratory health and exposure assessment tools have improved dramatically in recent years. We present "summary observations" and "knowledge gaps." We end by discussing what is known about what can be done at the individual/household, local/regional, and national levels to overcome structural impediments, reduce air pollution exposures, and improve child lung function. We found a large literature on adverse air pollution effects on children's lung function level and growth; however, many questions remain. Important areas needing further research include whether early-life effects are fixed or reversible; and what are windows of increased susceptibility, long-term effects of repeated wildfire events, and effects of air quality interventions.
Topics: Air Pollutants; Air Pollution; Animals; Child; Environmental Exposure; Humans; Lung; Particulate Matter
PubMed: 34238501
DOI: 10.1016/j.jaci.2021.05.006 -
Proceedings of the National Academy of... Feb 2022Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based...
Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography-mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 () mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.
Topics: Animals; Drug Delivery Systems; Female; Gene Transfer Techniques; Genetic Engineering; Liposomes; Lung; Lung Diseases; Lymphangioleiomyomatosis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Protein Corona; RNA, Messenger; RNA, Small Interfering
PubMed: 35173043
DOI: 10.1073/pnas.2116271119 -
Annals of the American Thoracic Society Nov 2019Pleuroparenchymal fibroelastosis (PPFE) is an unusual pulmonary disease with unique clinical, radiological, and pathological characteristics. Designated a rare... (Review)
Review
Pleuroparenchymal fibroelastosis (PPFE) is an unusual pulmonary disease with unique clinical, radiological, and pathological characteristics. Designated a rare idiopathic interstitial pneumonia in 2013, its name refers to a combination of fibrosis involving the visceral pleura and fibroelastotic changes predominating in the subpleural lung parenchyma. Although a number of disease associations have been described, no single cause of PPFE has been unequivocally identified. A diagnosis of PPFE is most commonly achieved by identifying characteristic abnormalities on computed tomographic scans. The earliest changes are consistently located in the upper lobes close to the lung apices, the same locations where subsequent disease progression is also most conspicuous. When sufficiently severe, the disease leads to progressive volume loss of the upper lobes, which, in combination with decreased body mass, produces platythorax. Once regarded as a slowly progressing entity, it is now acknowledged that some patients with PPFE follow an inexorably progressive course that culminates in irreversible respiratory failure and early death. In the absence of effective medical drug treatment, lung transplant remains the only therapeutic option for this disorder. This review focuses on improving early disease recognition and evaluating its pathophysiological impact and discusses working approaches for its management.
Topics: Bone Marrow Transplantation; Fibrosis; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Lung Transplantation; Pleura; Pulmonary Fibrosis; Tomography, X-Ray Computed
PubMed: 31425665
DOI: 10.1513/AnnalsATS.201902-181CME -
Science Immunology Oct 2020Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage... (Observational Study)
Observational Study
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression () is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
Topics: Administration, Inhalation; Adoptive Transfer; Adult; Aged; Animals; Bleomycin; Bronchoalveolar Lavage Fluid; Bronchoscopy; Carboxy-Lyases; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Female; Fibroblasts; Healthy Volunteers; Humans; Hydro-Lyases; Idiopathic Pulmonary Fibrosis; Lung; Macrophages, Alveolar; Male; Mice; Mice, Knockout; Middle Aged; Primary Cell Culture; Severity of Illness Index; Succinates
PubMed: 33097591
DOI: 10.1126/sciimmunol.abc1884 -
Journal of the American Veterinary... Nov 2021To provide updated information on the distribution of histopathologic types of primary pulmonary neoplasia in dogs and evaluate the effect of postoperative adjuvant...
OBJECTIVE
To provide updated information on the distribution of histopathologic types of primary pulmonary neoplasia in dogs and evaluate the effect of postoperative adjuvant chemotherapy in dogs with pulmonary carcinoma.
ANIMALS
340 dogs.
PROCEDURES
Medical records of dogs that underwent lung lobectomy for removal of a primary pulmonary mass were reviewed, and histopathologic type of lesions was determined. The canine lung carcinoma stage classification system was used to determine clinical stage for dogs with pulmonary carcinoma.
RESULTS
Pulmonary carcinoma was the most frequently encountered tumor type (296/340 [87.1%]), followed by sarcoma (26 [7.6%]), adenoma (11 [3.2%]), and pulmonary neuroendocrine tumor (5 [1.5%]); there was also 1 plasmacytoma and 1 carcinosarcoma. Twenty (5.9%) sarcomas were classified as primary pulmonary histiocytic sarcoma. There was a significant difference in median survival time between dogs with pulmonary carcinomas (399 days), dogs with histiocytic sarcomas (300 days), and dogs with neuroendocrine tumors (498 days). When dogs with pulmonary carcinomas were grouped on the basis of clinical stage, there were no significant differences in median survival time between dogs that did and did not receive adjuvant chemotherapy.
CLINICAL RELEVANCE
Results indicated that pulmonary carcinoma is the most common cause of primary pulmonary neoplasia in dogs; however, nonepithelial tumors can occur. Survival times were significantly different between dogs with pulmonary carcinoma, histiocytic sarcoma, and neuroendocrine tumor, emphasizing the importance of recognizing the relative incidence of these various histologic diagnoses. The therapeutic effect of adjuvant chemotherapy in dogs with pulmonary carcinoma remains unclear and warrants further investigation.
Topics: Animals; Dog Diseases; Dogs; Histiocytic Sarcoma; Lung; Lung Neoplasms; Retrospective Studies
PubMed: 34851850
DOI: 10.2460/javma.20.12.0698 -
Pharmacological Research Aug 2022The role of gut microbiota in regulating the intestinal homeostasis, as well as the pathogenesis of severe acute pancreatitis-associated lung injury (PALI) is widely... (Review)
Review
The role of gut microbiota in regulating the intestinal homeostasis, as well as the pathogenesis of severe acute pancreatitis-associated lung injury (PALI) is widely recognized. The bioactive functions of metabolites with small molecule weight and the detail molecular mechanisms of PALI mediated by "gut-lung axis" have gradually raised the attentions of researchers. Several studies have proved that short-chain fatty acids (SCFAs) produced by gut microbiome play crucial roles and varied activities in the process of PALI. However, relevant reviews reporting SCFAs in the involvement of PALI is lacking. In this review, we firstly introduced the synthetic and metabolic pathways of SCFAs, as well as the transport and signal transduction routes in brief. Afterwards, we focused on the possible mechanisms and clues of SCFAs to participate in the fight against PALI which referred to the inhibition of pathogen proliferation, anti-inflammatory effects, enhancement of intestinal barrier functions, and the maintenance and regulation of immune homeostasis via pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In addition, the latest reported pathological and physiological mechanisms of the gut-lung axis involved in PALI were reviewed. Finally, we summarized the potential therapeutic interventions of PALI by targeting SCFAs, including dietary fiber supplementation, direct supplementation of SCFAs/prebiotics/probiotics, and drugs administration, which is expected to provide new sights for clinical use in the future.
Topics: Acute Disease; Fatty Acids, Volatile; Gastrointestinal Microbiome; Humans; Lung; Lung Injury; Pancreatitis
PubMed: 35752356
DOI: 10.1016/j.phrs.2022.106321 -
The European Respiratory Journal Apr 2023Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) with endobronchial valves can improve outcomes in appropriately selected patients... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) with endobronchial valves can improve outcomes in appropriately selected patients with emphysema. However, no direct comparison data exist to inform clinical decision making in people who appear suitable for both procedures. Our aim was to investigate whether LVRS produces superior health outcomes when compared with BLVR at 12 months.
METHODS
This multicentre, single-blind, parallel-group trial randomised patients from five UK hospitals, who were suitable for a targeted lung volume reduction procedure, to either LVRS or BLVR and compared outcomes at 1 year using the i-BODE score. This composite disease severity measure includes body mass index, airflow obstruction, dyspnoea and exercise capacity (incremental shuttle walk test). The researchers responsible for collecting outcomes were masked to treatment allocation. All outcomes were assessed in the intention-to-treat population.
RESULTS
88 participants (48% female, mean±sd age 64.6±7.7 years, forced expiratory volume in 1 s percent predicted 31.0±7.9%) were recruited at five specialist centres across the UK and randomised to either LVRS (n=41) or BLVR (n=47). At 12 months follow-up, the complete i-BODE was available in 49 participants (21 LVRS/28 BLVR). Neither improvement in the i-BODE score (LVRS -1.10±1.44 BLVR -0.82±1.61; p=0.54) nor in its individual components differed between groups. Both treatments produced similar improvements in gas trapping (residual volume percent predicted: LVRS -36.1% (95% CI -54.6- -10%) BLVR -30.1% (95% CI -53.7- -9%); p=0.81). There was one death in each treatment arm.
CONCLUSION
Our findings do not support the hypothesis that LVRS is a substantially superior treatment to BLVR in individuals who are suitable for both treatments.
Topics: Humans; Female; Middle Aged; Aged; Male; Pneumonectomy; Single-Blind Method; Lung; Pulmonary Emphysema; Forced Expiratory Volume; Treatment Outcome; Bronchoscopy
PubMed: 36796833
DOI: 10.1183/13993003.02063-2022 -
Frontiers in Immunology 2023CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against...
RATIONALE
CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated.
OBJECTIVES
We sought to determine if CC16 deficiency impairs epithelial-driven host responses and identify novel receptors expressed within the pulmonary epithelium through which CC16 imparts activity.
METHODS
We utilized mass spectrometry and quantitative proteomics to investigate how CC16 deficiency impacts apically secreted pulmonary epithelial proteins. Mouse tracheal epithelial cells (MTECS), human nasal epithelial cells (HNECs) and mice were studied in naïve conditions and after Mp challenge.
MEASUREMENTS AND MAIN RESULTS
We identified 8 antimicrobial proteins significantly decreased by CC16 MTECS, 6 of which were validated by mRNA expression in Severe Asthma Research Program (SARP) cohorts. Short Palate Lung and Nasal Epithelial Clone 1 (SPLUNC1) was the most differentially expressed protein (66-fold) and was the focus of this study. Using a combination of MTECs and HNECs, we found that CC16 enhances pulmonary epithelial-driven SPLUNC1 expression via signaling through the receptor complex Very Late Antigen-2 (VLA-2) and that rCC16 given to mice enhances pulmonary SPLUNC1 production and decreases (Mp) burden. Likewise, rSPLUNC1 results in decreased Mp burden in mice lacking CC16 mice. The VLA-2 integrin binding site within rCC16 is necessary for induction of SPLUNC1 and the reduction in Mp burden.
CONCLUSION
Our findings demonstrate a novel role for CC16 in epithelial-driven host defense by up-regulating antimicrobials and define a novel epithelial receptor for CC16, VLA-2, through which signaling is necessary for enhanced SPLUNC1 production.
Topics: Animals; Humans; Mice; Asthma; Integrin alpha2beta1; Lung; Mycoplasma pneumoniae; Signal Transduction
PubMed: 38053993
DOI: 10.3389/fimmu.2023.1277582 -
Journal of Ethnopharmacology Jan 2023Acute lung injury (ALI) is a common manifestation of COVID-19. Xuanfei Baidu Formula(XFBD) is used in China to treat mild or common damp-toxin obstructive pulmonary...
ETHNOPHARMACOLOGICAL RELEVANCE
Acute lung injury (ALI) is a common manifestation of COVID-19. Xuanfei Baidu Formula(XFBD) is used in China to treat mild or common damp-toxin obstructive pulmonary syndrome in COVID-19 patients. However, the active ingredients of XFBD have not been extensively studied, and its mechanism of action in the treatment of ALI is not well understood.
AIM OF THE STUDY
The purpose of this study was to investigate the mechanism of action of XFBD in treating ALI in rats, by evaluating its active components.
MATERIALS AND METHODS
Firstly, the chemical composition of XFBD was identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry. The potential targets of XFBD for ALI treatment were predicted using network pharmacological analysis. Finally, the molecular mechanism of XFBD was validated using a RAW264.7 cell inflammation model and a mouse ALI model.
RESULTS
A total of 113 compounds were identified in XFBD. Network pharmacology revealed 34 hub targets between the 113 compounds and ALI. The results of Kyoto Encyclopedia of Genes and Genomes and gene ontology analyses indicated that the NF-κB signaling pathway was the main pathway for XFBD in the treatment of ALI. We found that XFBD reduced proinflammatory factor levels in LPS-induced cellular models. By examining the lung wet/dry weight ratio and pathological sections in vivo, XFBD was found that XFBD could alleviate ALI. Immunohistochemistry results showed that XFBD inhibited ALI-induced increases in p-IKK, p-NF-κB p65, and iNOS proteins. In vitro experiments demonstrated that XFBD inhibited LPS-induced activation of the NF-κB pathway.
CONCLUSION
This study identified the potential practical components of XFBD, combined with network pharmacology and experimental validation to demonstrate that XFBD can alleviate lung injury caused by ALI by inhibiting the NF-κB signaling pathway.
Topics: Mice; Rats; Animals; NF-kappa B; Lipopolysaccharides; COVID-19; Acute Lung Injury; Signal Transduction; Lung; Disease Models, Animal
PubMed: 36252879
DOI: 10.1016/j.jep.2022.115833 -
International Journal of Molecular... Jun 2023Asthma is a heterogenous chronic inflammatory lung disease with endotypes that manifest different immune system profiles, severity, and responses to current therapies.... (Review)
Review
Asthma is a heterogenous chronic inflammatory lung disease with endotypes that manifest different immune system profiles, severity, and responses to current therapies. Regardless of endotype, asthma features increased immune cell infiltration, inflammatory cytokine release, and airway remodeling. Lung macrophages are also heterogenous in that there are separate subsets and, depending on the environment, different effector functions. Lung macrophages are important in recruitment of immune cells such as eosinophils, neutrophils, and monocytes that enhance allergic inflammation and initiate T helper cell responses. Persistent lung remodeling including mucus hypersecretion, increased airway smooth muscle mass, and airway fibrosis contributes to progressive lung function decline that is insensitive to current asthma treatments. Macrophages secrete inflammatory mediators that induce airway inflammation and remodeling. Additionally, lung macrophages are instrumental in protecting against pathogens and play a critical role in resolution of inflammation and return to homeostasis. This review summarizes current literature detailing the roles and existing knowledge gaps for macrophages as key inflammatory orchestrators in asthma pathogenesis. We also raise the idea that modulating inflammatory responses in lung macrophages is important for alleviating asthma.
Topics: Humans; Asthma; Lung; Inflammation; Macrophages; Cytokines; Airway Remodeling
PubMed: 37445635
DOI: 10.3390/ijms241310451