-
Radiologia Dec 2022The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually...
The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually contain air. The differential diagnosis of these lesions can be challenging, requiring both clinical and radiological perspectives. Entities such as pulmonary emphysema and cystic bronchiectasis can simulate cystic disease. High-resolution computed tomography (HRCT) is the imaging technique of choice for the evaluation and diagnosis of cystic lung disease, because it confirms the presence of lung disease and establishes the correct diagnosis of the associated complications. In many cases, the diagnosis can be established based on the HRCT findings, thus making histologic confirmation unnecessary. For these reasons, radiologists need to be familiar with the different presentations of these entities. A wide variety of diseases are characterised by the presence of diffuse pulmonary cysts. Among these, the most common are lymphangioleiomyomatosis, which may or may not be associated with tuberous sclerosis, Langerhans cell histiocytosis, and lymphocytic interstitial pneumonia. Other, less common entities include Birt-Hogg-Dubé syndrome, amyloidosis, and light-chain deposit disease. This article describes the characteristics and presentations of some of these entities, emphasizing the details that can help differentiate among them.
Topics: Humans; Lung Diseases, Interstitial; Lung; Lymphangioleiomyomatosis; Histiocytosis, Langerhans-Cell; Cysts
PubMed: 36737165
DOI: 10.1016/j.rxeng.2022.09.005 -
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 -
Korean Journal of Radiology Sep 2019Lung cysts are commonly seen on computed tomography (CT), and cystic lung diseases show a wide disease spectrum. Thus, correct diagnosis of cystic lung diseases is a... (Review)
Review
Lung cysts are commonly seen on computed tomography (CT), and cystic lung diseases show a wide disease spectrum. Thus, correct diagnosis of cystic lung diseases is a challenge for radiologists. As the first diagnostic step, cysts should be distinguished from cavities, bullae, pneumatocele, emphysema, honeycombing, and cystic bronchiectasis. Second, cysts can be categorized as single/localized versus multiple/diffuse. Solitary/localized cysts include incidental cysts and congenital cystic diseases. Multiple/diffuse cysts can be further categorized according to the presence or absence of associated radiologic findings. Multiple/diffuse cysts without associated findings include lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome. Multiple/diffuse cysts may be associated with ground-glass opacity or small nodules. Multiple/diffuse cysts with nodules include Langerhans cell histiocytosis, cystic metastasis, and amyloidosis. Multiple/diffuse cysts with ground-glass opacity include pneumocystis pneumonia, desquamative interstitial pneumonia, and lymphocytic interstitial pneumonia. This stepwise radiologic diagnostic approach can be helpful in reaching a correct diagnosis for various cystic lung diseases.
Topics: Amyloidosis; Birt-Hogg-Dube Syndrome; Cysts; Diagnosis, Differential; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Lymphangioleiomyomatosis; Pneumonia, Pneumocystis; Tomography, X-Ray Computed
PubMed: 31464115
DOI: 10.3348/kjr.2019.0057 -
American Journal of Respiratory and... Nov 2020Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic...
Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. Identification and characterization of LAM cells in human lung and uterus using a single-cell approach. Single-cell and single-nuclei RNA sequencing on LAM ( = 4) and control ( = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAM cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM. A unique cell type termed LAM was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAM cells expressing signature genes included known LAM markers such as , , , and and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic mutations, supporting a potential uterine origin for the LAM cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. A unique population of LAM cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.
Topics: Adult; Aged; Biomarkers, Tumor; Female; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Middle Aged; Single-Cell Analysis; Transcriptome; United States; Uterine Neoplasms
PubMed: 32603599
DOI: 10.1164/rccm.201912-2445OC -
Thorax Jan 2023Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the lung and progressive respiratory failure. The cellular composition,...
Lymphangioleiomyomatosis (LAM) is a rare lung disease of women, causing cystic remodelling of the lung and progressive respiratory failure. The cellular composition, microenvironment and cellular interactions within the LAM lesion remain unclear. To facilitate data sharing and collaborative LAM research, we performed an integrative analysis of single-cell data compiled from lung, uterus and kidney of patients with LAM from three research centres and developed an LAM Cell Atlas (LCA) Web-Portal. The LCA offers a variety of interactive options for investigators to search, visualise and reanalyse comprehensive single-cell multiomics data sets to reveal dysregulated genetic programmes at transcriptomic, epigenomic and cell-cell connectome levels.
Topics: Humans; Female; Lymphangioleiomyomatosis; Lung Diseases; Lung; Respiratory Insufficiency; Transcriptome; Lung Neoplasms; Tumor Microenvironment
PubMed: 36599466
DOI: 10.1136/thoraxjnl-2022-218772 -
The New England Journal of Medicine Jun 2018
Topics: Adult; Antibiotics, Antineoplastic; Chest Pain; Dyspnea; Female; Forced Expiratory Volume; Humans; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Pleurodesis; Sirolimus; Tomography, X-Ray Computed
PubMed: 29874537
DOI: 10.1056/NEJMicm1712581 -
Immunology and Allergy Clinics of North... May 2023Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤2 mm) from cavities and characterize... (Review)
Review
Cysts and cavities in the lung are commonly encountered on chest imaging. It is necessary to distinguish thin-walled lung cysts (≤2 mm) from cavities and characterize their distribution as focal or multifocal versus diffuse. Focal cavitary lesions are often caused by inflammatory, infectious, or neoplastic processes in contrast to diffuse cystic lung diseases. An algorithmic approach to diffuse cystic lung disease can help narrow the differential diagnosis, and additional testing such as skin biopsy, serum biomarkers, and genetic testing can be confirmatory. An accurate diagnosis is essential for the management and disease surveillance of extrapulmonary complications.
Topics: Humans; Lymphangioleiomyomatosis; Histiocytosis, Langerhans-Cell; Birt-Hogg-Dube Syndrome; Tomography, X-Ray Computed; Lung Diseases; Lung; Cysts; Diagnosis, Differential
PubMed: 37055093
DOI: 10.1016/j.iac.2023.01.003 -
American Journal of Physiology. Cell... Feb 2023Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers,... (Review)
Review
Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, caused by somatic mutations in the TSC1 or TSC2 genes, and driven by estrogen. Similar to many cancers, it is metastatic, primarily to the lung. Despite its monogenetic nature, like many cancers, LAM is a heterogeneous disease. The cellular constituents of LAM are very diverse, including mesenchymal, epithelial, endothelial, and immune cells. LAM is characterized by dysregulation of many cell signaling pathways, distinct populations of LAM cells, and a rich microenvironment, in which the immune system appears to play an important role. This review delineates the heterogeneity of LAM and focuses on the metastatic features of LAM, the deregulated signaling mechanisms and the tumor microenvironment. Understanding the tumor-host interaction in LAM may provide insights into the development of new therapeutic strategies, which could be combinatorial or superlative to Sirolimus, the current U.S. Food and Drug Administration-approved treatment.
Topics: Humans; Female; Lymphangioleiomyomatosis; Tumor Suppressor Proteins; Tuberous Sclerosis Complex 2 Protein; Lung; Lung Neoplasms; Tumor Microenvironment
PubMed: 36571446
DOI: 10.1152/ajpcell.00202.2022 -
European Respiratory Review : An... Sep 2020Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a...
Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a characteristic computed tomography scan pattern that allows diagnosis. The pathogenetic mechanisms underlying cyst formation in the lung are still not clear and a number of hypotheses have been postulated according to the different aetiologies: ball-valve effect, ischaemic dilatation of small airways and alveoli related to infiltration and obstruction of small vessels and capillaries that supply the terminal bronchioles and connective tissue degradation by matrix metalloproteases. A wide number of lung cyst diseases have been classified into six diagnostic groups according to the aetiology: neoplastic, congenital/genetic, lymphoproliferative, infective, associated with interstitial lung diseases, and other causes. This article focuses on lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and Erdheim-Chester disease, Birt-Hogg-Dubé, follicular bronchiolitis and lymphocytic interstitial pneumonia, light-chain deposition disease and amyloidosis, congenital lung disease associated with aberrant lung development and growth, and cystic lung disease associated with neoplastic lesion. These cystic diseases are epidemiologically considered as ultra-rare conditions as they affect fewer than one individual per 50 000 or fewer than 20 individuals per million. Despite the rarity of this group of disorders, the increasing use of high-resolution computed tomography has improved the diagnostic yield, even in asymptomatic patients allowing prompt and correct therapy and management without the need for a biopsy.
Topics: Birt-Hogg-Dube Syndrome; Diagnosis, Differential; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Lung Diseases, Interstitial; Lymphangioleiomyomatosis
PubMed: 32878971
DOI: 10.1183/16000617.0163-2019 -
The European Respiratory Journal May 2006Lymphangioleiomyomatosis (LAM) is a rare disease of the lungs and lymphatics, which can occur sporadically or in association with tuberous sclerosis. LAM almost... (Review)
Review
Lymphangioleiomyomatosis (LAM) is a rare disease of the lungs and lymphatics, which can occur sporadically or in association with tuberous sclerosis. LAM almost exclusively affects females, generally developing before the menopause. The disease is characterised by progressive pulmonary cystic change, recurrent pneumothorax, chylous pleural collections and, in most cases, progressive respiratory failure. Abdominal manifestations include lymphadenopathy, cystic lymphatic masses (lymphangioleiomyomas), chylous ascites and angiomyolipoma (a benign tumour). Survival in LAM is approximately 70% at 10 yrs, although this is highly variable since long-term survivors have been described. Diagnosis is made by a combination of clinical features and computed tomography scanning or, in cases of doubt, lung biopsy. In patients with rapidly progressive disease, hormone treatment (predominantly progesterone) has been used, although no firm evidence supports its use. Otherwise, treatment is aimed at complications including pneumothorax, chylous collections and extrapulmonary manifestations. The only treatment for severe LAM is currently lung transplantation. Recent developments in the cell biology of lymphangioleiomyomatosis have shown that these patients have somatic mutations in the genes linked to tuberous sclerosis and that rapamycin may correct the resulting cellular abnormality. Trials of rapamycin in lymphangioleiomyomatosis are currently underway and offer hope of evidence-based treatment for the disease.
Topics: Humans; Lymphangioleiomyomatosis
PubMed: 16707400
DOI: 10.1183/09031936.06.00113303