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Modern Pathology : An Official Journal... Jan 2022The clinical and pathologic diagnosis of hypersensitivity pneumonitis has been confounded by conflicting definitions, with two recent guidelines suggesting that... (Review)
Review
The clinical and pathologic diagnosis of hypersensitivity pneumonitis has been confounded by conflicting definitions, with two recent guidelines suggesting that hypersensitivity pneumonitis simply be diagnosed as nonfibrotic or fibrotic. Nonfibrotic hypersensitivity pneumonitis is usually characterized by a bronchiolocentric chronic interstitial inflammatory infiltrate, frequently but by no means always with associated granulomas or giant cells. Fibrotic hypersensitivity pneumonitis may take the form of interstitial fibrosis confined to the peribronchiolar regions, or fibrotic nonspecific interstitial pneumonia, or a process similar to and sometimes indistinguishable from usual interstitial pneumonia/idiopathic interstitial fibrosis, but the exact pathologic features that favor a diagnosis of fibrotic hypersensitivity pneumonitis are disputed. Granulomas/giant cells are much less frequent in fibrotic compared to nonfibrotic hypersensitivity pneumonitis. Extensive peribronchiolar metaplasia, particularly peribronchiolar metaplasia affecting more than half the bronchioles, supports a diagnosis of fibrotic hypersensitivity pneumonitis over usual interstitial pneumonia, as does the presence of predominantly peribronchiolar disease with relative subpleural sparing. Clinical and CT features are crucial to the diagnosis of hypersensitivity pneumonitis: sparing of the lung bases, centrilobular nodules, air-trapping, or the triple density sign with fibrosis favor a diagnosis of fibrotic hypersensitivity pneumonitis. At this point there are no molecular tests that reliably separate fibrotic hypersensitivity pneumonitis from other forms of interstitial lung disease. Currently the separation of fibrotic hypersensitivity pneumonitis from usual interstitial pneumonia is crucial to treatment (immunosuppressives for the former, anti-fibrotics for the latter) but this approach is changing and all progressive fibrosing interstitial pneumonias will probably be treated with antifibrotics in the future.
Topics: Alveolitis, Extrinsic Allergic; Biopsy; Diagnosis, Differential; Humans; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial
PubMed: 34531525
DOI: 10.1038/s41379-021-00866-y -
Chest Jul 2022Organizing pneumonia (OP), characterized histopathologically by patchy filling of alveoli and bronchioles by loose plugs of connective tissue, may be seen in a variety... (Review)
Review
Organizing pneumonia (OP), characterized histopathologically by patchy filling of alveoli and bronchioles by loose plugs of connective tissue, may be seen in a variety of conditions. These include but are not limited to after an infection, drug reactions, radiation therapy, and collagen vascular diseases. When a specific cause is responsible for this entity, it is referred to as "secondary OP." When an extensive search fails to reveal a cause, it is referred to as "cryptogenic OP" (previously called "bronchiolitis obliterans with OP"), which is a clinical, radiologic, and pathologic entity classified as an interstitial lung disease. The clinical presentation of OP often mimics that of other disorders, such as infection and cancer, which can result in a delay in diagnosis and inappropriate management of the underlying disease. The radiographic presentation of OP is polymorphous but often has subpleural consolidations with air bronchograms or solitary or multiple nodules, which can wax and wane. Diagnosis of OP sometimes requires histopathologic confirmation and exclusion of other possible causes. Treatment usually requires a prolonged steroid course, and disease relapse is common. The aim of this article is to summarize the clinical, radiographic, and histologic presentations of this disease and to provide a practical diagnostic algorithmic approach incorporating clinical history and characteristic imaging patterns.
Topics: Bronchiolitis Obliterans; Cryptogenic Organizing Pneumonia; Humans; Lung; Lung Diseases, Interstitial; Pneumonia
PubMed: 35038455
DOI: 10.1016/j.chest.2021.12.659 -
Nature Apr 2022Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a...
Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5 fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5 fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.
Topics: Alveolar Epithelial Cells; Animals; Cell Differentiation; Cell Lineage; Connectome; Fibroblasts; Gene Expression Profiling; Humans; Lung; Lung Diseases; Mice; Organoids; Primates; Regeneration; Single-Cell Analysis; Stem Cells
PubMed: 35355018
DOI: 10.1038/s41586-022-04541-3 -
Nature Dec 2020The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly...
The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5 basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5 cells in basal organoids revealed a distinct population of ITGA6ITGB4 mitotic cells, whose offspring further segregated into a TNFRSF12A subfraction that comprised about ten per cent of KRT5 basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.
Topics: Alveolar Epithelial Cells; COVID-19; Cell Differentiation; Cell Division; Clone Cells; Humans; In Vitro Techniques; Influenza A Virus, H1N1 Subtype; Integrin alpha6; Integrin beta4; Keratin-5; Lung; Models, Biological; Organoids; Pneumonia, Viral; SARS-CoV-2; Single-Cell Analysis; TWEAK Receptor; Tissue Culture Techniques
PubMed: 33238290
DOI: 10.1038/s41586-020-3014-1 -
Matter Sep 2022Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present...
Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.
PubMed: 35847197
DOI: 10.1016/j.matt.2022.06.012