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Cell and Tissue Research Mar 2017The study of the structural basis of gas exchange function in the lung depends on the availability of quantitative information that concerns the structures establishing... (Review)
Review
The study of the structural basis of gas exchange function in the lung depends on the availability of quantitative information that concerns the structures establishing contact between the air in the alveoli and the blood in the alveolar capillaries, which can be entered into physiological equations for predicting oxygen uptake. This information is provided by morphometric studies involving stereological methods and allows estimates of the pulmonary diffusing capacity of the human lung that agree, in experimental studies, with the maximal oxygen consumption. The basis for this "machine lung" structure lies in the complex design of the cells building an extensive air-blood barrier with minimal cell mass.
Topics: Animals; Diffusion; Gases; Humans; Lung
PubMed: 27981379
DOI: 10.1007/s00441-016-2541-4 -
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 -
American Journal of Respiratory Cell... Jul 2022Immune cells have been implicated in idiopathic pulmonary fibrosis (IPF), but the phenotypes and effector mechanisms of these cells remain incompletely characterized. We...
Immune cells have been implicated in idiopathic pulmonary fibrosis (IPF), but the phenotypes and effector mechanisms of these cells remain incompletely characterized. We performed mass cytometry to quantify immune cell subsets in lungs of 12 patients with IPF and 15 organ donors without chronic lung disease and used existing single-cell RNA-sequencing data to investigate transcriptional profiles of immune cells overrepresented in IPF. Among myeloid cells, we found increased numbers of alveolar macrophages (AMØs) and dendritic cells (DCs) in IPF, as well as a subset of monocyte-derived DCs. In contrast, monocyte-like cells and interstitial macrophages were reduced in IPF. Transcriptomic profiling identified an enrichment for IFN-γ response pathways in AMØs and DCs from IPF, as well as antigen processing in DCs and phagocytosis in AMØs. Among T cells, we identified three subsets of memory T cells that were increased in IPF, including CD4 and CD8 resident memory T cells (T) and CD8 effector memory cells. The response to the IFN-γ pathway was enriched in CD4 T and CD8 T cells in IPF, together with T cell activation and immune response-regulating signaling pathways. Increased AMØs, DCs, and memory T cells were present in IPF lungs compared with control subjects. In IPF, these cells possess an activation profile indicating increased IFN-γ signaling and upregulation of adaptive immunity in the lungs. Together, these studies highlight critical features of the immunopathogenesis of IPF.
Topics: Gene Expression Profiling; Humans; Idiopathic Pulmonary Fibrosis; Lung; Macrophages, Alveolar; Single-Cell Analysis
PubMed: 35468042
DOI: 10.1165/rcmb.2021-0418OC -
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 -
Anesthesiology Nov 2020Prone ventilation redistributes lung inflation along the gravitational axis; however, localized, nongravitational effects of body position are less well characterized....
BACKGROUND
Prone ventilation redistributes lung inflation along the gravitational axis; however, localized, nongravitational effects of body position are less well characterized. The authors hypothesize that positional inflation improvements follow both gravitational and nongravitational distributions. This study is a nonoverlapping reanalysis of previously published large animal data.
METHODS
Five intubated, mechanically ventilated pigs were imaged before and after lung injury by tracheal injection of hydrochloric acid (2 ml/kg). Computed tomography scans were performed at 5 and 10 cm H2O positive end-expiratory pressure (PEEP) in both prone and supine positions. All paired prone-supine images were digitally aligned to each other. Each unit of lung tissue was assigned to three clusters (K-means) according to positional changes of its density and dimensions. The regional cluster distribution was analyzed. Units of tissue displaying lung recruitment were mapped.
RESULTS
We characterized three tissue clusters on computed tomography: deflation (increased tissue density and contraction), limited response (stable density and volume), and reinflation (decreased density and expansion). The respective clusters occupied (mean ± SD including all studied conditions) 29.3 ± 12.9%, 47.6 ± 11.4%, and 23.1 ± 8.3% of total lung mass, with similar distributions before and after lung injury. Reinflation was slightly greater at higher PEEP after injury. Larger proportions of the reinflation cluster were contained in the dorsal versus ventral (86.4 ± 8.5% vs. 13.6 ± 8.5%, P < 0.001) and in the caudal versus cranial (63.4 ± 11.2% vs. 36.6 ± 11.2%, P < 0.001) regions of the lung. After injury, prone positioning recruited 64.5 ± 36.7 g of tissue (11.4 ± 6.7% of total lung mass) at lower PEEP, and 49.9 ± 12.9 g (8.9 ± 2.8% of total mass) at higher PEEP; more than 59.0% of this recruitment was caudal.
CONCLUSIONS
During mechanical ventilation, lung reinflation and recruitment by the prone positioning were primarily localized in the dorso-caudal lung. The local effects of positioning in this lung region may determine its clinical efficacy.
Topics: Animals; Lung; Models, Animal; Prone Position; Pulmonary Ventilation; Respiration, Artificial; Supine Position; Swine; Tomography, X-Ray Computed
PubMed: 32773690
DOI: 10.1097/ALN.0000000000003509 -
American Journal of Respiratory and... Jan 2021Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte... (Clinical Trial)
Clinical Trial Comparative Study
Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis. To phenotype patients with IPF for potential targeted therapy, we developed Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2 monocytes and macrophages using positron emission tomography (PET). CCR2 cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2 cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and RNA hybridization and then correlated with parallel quantitation of lung uptake by Cu-DOTA-ECL1i PET. Mouse models established that increased Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2 cell infiltration associated with fibrosis ( = 72). As therapeutic models, the inhibition of fibrosis by IL-1β blockade ( = 19) or antifibrotic pirfenidone ( = 18) reduced CCR2 macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2 cells concentrated in perifibrotic regions and correlated with radiotracer localization ( = 21). Human imaging revealed little lung uptake in healthy volunteers ( = 7), whereas subjects with IPF ( = 4) exhibited intensive signals in fibrotic zones. These findings support a role for imaging CCR2 cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).
Topics: Adult; Aged; Aged, 80 and over; Animals; Biomarkers; Disease Models, Animal; Female; Humans; Idiopathic Pulmonary Fibrosis; Lung; Macrophages; Male; Mice; Middle Aged; Molecular Imaging; Monocytes; Positron-Emission Tomography; Receptors, CCR2
PubMed: 32673071
DOI: 10.1164/rccm.202004-1132OC -
Novel FOXF1-Stabilizing Compound TanFe Stimulates Lung Angiogenesis in Alveolar Capillary Dysplasia.American Journal of Respiratory and... Apr 2023Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is linked to heterozygous mutations in the (Forkhead Box F1) gene, a key transcriptional...
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is linked to heterozygous mutations in the (Forkhead Box F1) gene, a key transcriptional regulator of pulmonary vascular development. There are no effective treatments for ACDMPV other than lung transplant, and new pharmacological agents activating FOXF1 signaling are urgently needed. Identify-small molecule compounds that stimulate FOXF1 signaling. We used mass spectrometry, immunoprecipitation, and the ubiquitination assay to identify TanFe (transcellular activator of nuclear FOXF1 expression), a small-molecule compound from the nitrile group, which stabilizes the FOXF1 protein in the cell. The efficacy of TanFe was tested in mouse models of ACDMPV and acute lung injury and in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV. We identified HECTD1 as an E3 ubiquitin ligase involved in ubiquitination and degradation of the FOXF1 protein. The TanFe compound disrupted FOXF1-HECTD1 protein-protein interactions and decreased ubiquitination of the FOXF1 protein in pulmonary endothelial cells . TanFe increased protein concentrations of FOXF1 and its target genes , , and in LPS-injured mouse lungs, decreasing endothelial permeability and inhibiting lung inflammation. Treatment of pregnant mice with TanFe increased FOXF1 protein concentrations in lungs of embryos, stimulated neonatal lung angiogenesis, and completely prevented the mortality of mice after birth. TanFe increased angiogenesis in human vascular organoids derived from induced pluripotent stem cells of a patient with ACDMPV with deletion. TanFe is a novel activator of FOXF1, providing a new therapeutic candidate for treatment of ACDMPV and other neonatal pulmonary vascular diseases.
Topics: Infant, Newborn; Humans; Animals; Mice; Persistent Fetal Circulation Syndrome; Endothelial Cells; Lung; Forkhead Transcription Factors
PubMed: 36480964
DOI: 10.1164/rccm.202207-1332OC -
Ghana Medical Journal Jun 2020Pulmonary tuberculosis manifesting as a mass lesion, thus, mimicking a lung carcinoma is an unusual radiographic presentation of tuberculosis (TB). The common radiologic...
UNLABELLED
Pulmonary tuberculosis manifesting as a mass lesion, thus, mimicking a lung carcinoma is an unusual radiographic presentation of tuberculosis (TB). The common radiologic patterns and clinical presentations are well known and documented. We report two cases of pulmonary tuberculosis with a neoplastic appearance on chest imaging diagnosed histologically. A 21 - year old female with cough, weight loss, anorexia and an unremarkable physical examination. Chest radiography showed a right apical mass suggestive of lung cancer. Histology of the lesion revealed parenchymal pulmonary tuberculosis. A 49-year old male with left-sided chest pain, cough, anorexia, weight loss, mild pallor with an unremarkable chest examination. Chest imaging showed a left apical mass and mediastinal lymphadenopathy. Microscopic examination of the mass confirmed pulmonary tuberculosis. Pseudotumour pulmonary tuberculosis is a rare clinical entity that can lead to diagnostic challenges and must be considered in the differential diagnosis when mass lesions are seen on chest imaging, especially in TB endemic areas.
FUNDING
None declared.
Topics: Antitubercular Agents; Female; Humans; Lung; Male; Middle Aged; Radiography; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult
PubMed: 33536684
DOI: 10.4314/gmj.v54i2.12 -
Respiratory Medicine Jan 2022Pleuroparenchymal fibroelastosis (PPFE) is a rare, generally idiopathic form of interstitial pneumonia with unique clinical, radiological and histopathological features.... (Review)
Review
Pleuroparenchymal fibroelastosis (PPFE) is a rare, generally idiopathic form of interstitial pneumonia with unique clinical, radiological and histopathological features. It is named after the presence of upper lobe pleural and subjacent parenchymal fibrosis, with accompanying elastic fibers. Although it is usually an idiopathic disease, it has been linked to other co-existent diseases. Diagnostic suspicion of PPFE is based on the identification of typical abnormalities on chest CT scan, which are prevailingly located in the upper lobes, adjacent to the apex of the lungs. Diagnosis can be confirmed by histological analysis, although biopsy is not always feasible. The disease is generally progressive, but not uniformly. The course of the disease is frequently slow and involves a progressive loss of upper lobe volume, which results in platythorax, associated with a significant reduction of body mass. PPFE concomitant to other interstitial lung diseases is associated with a poorer prognosis. The disease occasionally progresses rapidly causing irreversible respiratory insufficiency, which leads to death. Currently, there is no effective pharmacological therapy available, and lung transplantation is the best therapeutic option. The purpose of this review is to draw the attention to PPFE, describe its clinical, radiological and histopathological features, analyze its diagnostic criteria, and provide an update on the management of the disease.
Topics: Humans; Lung; Lung Diseases, Interstitial; Lung Transplantation; Pleura; Tomography, X-Ray Computed
PubMed: 33992495
DOI: 10.1016/j.rmed.2021.106437 -
Saudi Medical Journal Oct 2022To present an unusual and a rare pulmonary affection by coronavirus disease-19 (COVID-19), in which only one lung is affected. Coronavirus disease-19 attacks the lungs... (Review)
Review
To present an unusual and a rare pulmonary affection by coronavirus disease-19 (COVID-19), in which only one lung is affected. Coronavirus disease-19 attacks the lungs and interferes seriously with their functions. The attack is usually bilaterally, while a uni lateral pulmonary affection is unusual. The presentation, both clinical and radiological findings, bronchoscopy appearance, the strange operative findings of the resected mass, the uneventful post-operative course, in addition to the histopathological report, will be presented.In conclusion, unilateral lung affection is unusual and post-viral pneumonia COVID-19 should be considered as a possible aftermath, which may not be uncommon in Iraq.
Topics: Humans; COVID-19; Pneumonia, Viral; Lung; Bronchoscopy; Iraq
PubMed: 36261211
DOI: 10.15537/smj.2022.43.10.20220294