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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 -
American Journal of Physiology. Cell... Oct 2023Pulmonary fibrosis results from a plethora of abnormal pathogenetic events. In idiopathic pulmonary fibrosis (IPF), inhalational, environmental, or occupational... (Review)
Review
Pulmonary fibrosis results from a plethora of abnormal pathogenetic events. In idiopathic pulmonary fibrosis (IPF), inhalational, environmental, or occupational exposures in genetically and epigenetically predisposed individuals trigger recurrent cycles of alveolar epithelial cell injury, activation of coagulation pathways, chemoattraction, and differentiation of monocytes into monocyte-derived alveolar macrophages (Mo-AMs). When these events happen intermittently and repeatedly throughout the individual's life cycle, the wound repair process becomes aberrant leading to bronchiolization of distal air spaces, fibroblast accumulation, extracellular matrix deposition, and loss of the alveolar-capillary architecture. The role of immune dysregulation in IPF pathogenesis and progression has been underscored in the past mainly after the disappointing results of immunosuppressant use in IPF patients; however, recent reports highlighting the prognostic and mechanistic roles of monocytes and Mo-AMs revived the interest in immune dysregulation in IPF. In this review, we will discuss the role of these cells in the onset and progression of IPF, as well as potential targeted therapies.
Topics: Humans; Monocytes; Idiopathic Pulmonary Fibrosis; Macrophages; Extracellular Matrix; Cell Differentiation; Lung
PubMed: 37694283
DOI: 10.1152/ajpcell.00302.2023 -
Nature Apr 2022The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive...
The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.
Topics: Animals; Bronchioles; Cell Lineage; Ferrets; Humans; Lung; Mice; Multipotent Stem Cells; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive
PubMed: 35355013
DOI: 10.1038/s41586-022-04552-0 -
Cell Stem Cell Aug 2014Respiratory disease is the third leading cause of death in the industrialized world. Consequently, the trachea, lungs, and cardiopulmonary vasculature have been the... (Review)
Review
Respiratory disease is the third leading cause of death in the industrialized world. Consequently, the trachea, lungs, and cardiopulmonary vasculature have been the focus of extensive investigations. Recent studies have provided new information about the mechanisms driving lung development and differentiation. However, there is still much to learn about the ability of the adult respiratory system to undergo repair and to replace cells lost in response to injury and disease. This Review highlights the multiple stem/progenitor populations in different regions of the adult lung, the plasticity of their behavior in injury models, and molecular pathways that support homeostasis and repair.
Topics: Animals; Bronchioles; Cell Differentiation; Cell Lineage; Epithelium; Homeostasis; Humans; Lung; Mesoderm; Mice; Pulmonary Alveoli; Regeneration; Respiration; Respiratory System; Signal Transduction; Stem Cells; Tissue Engineering; Trachea
PubMed: 25105578
DOI: 10.1016/j.stem.2014.07.012 -
American Journal of Respiratory Cell... Jun 2021Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease with underlying mechanisms that have been primarily investigated in mice after...
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease with underlying mechanisms that have been primarily investigated in mice after intratracheal instillation of a single dose of bleomycin. However, the model has significant limitations, including transient fibrosis that spontaneously resolves and its failure to fully recapitulate the epithelial remodeling in the lungs of patients with IPF. Thus, there remains an unmet need for a preclinical model with features that more closely resemble the human disease. Repetitive intratracheal instillation of bleomycin has previously been shown to recapitulate some of these features, but the instillation procedure is complex, and the long-term consequences on epithelial remodeling and fibrosis persistence and progression remain poorly understood. Here, we developed a simplified repetitive bleomycin instillation strategy consisting of three bi-weekly instillations that leads to persistent and progressive pulmonary fibrosis. Lung histology demonstrates increased collagen deposition, fibroblast accumulation, loss of type I and type II alveolar epithelial cells within fibrotic areas, bronchiolization of the lung parenchyma with CCSP cells, remodeling of the distal lung into cysts reminiscent of simple honeycombing, and accumulation of hyperplastic transitional KRT8 epithelial cells. Micro-computed tomographic imaging demonstrated significant traction bronchiectasis and subpleural fibrosis. Thus, the simplified repetitive bleomycin instillation strategy leads to progressive fibrosis and recapitulates the histological and radiographic characteristics of IPF. Compared with the single bleomycin instillation model, we suggest that the simplified repetitive instillation model may be better suited to address mechanistic questions about IPF pathogenesis and preclinical studies of antifibrotic drug candidates.
Topics: Animals; Bleomycin; Disease Progression; Epithelial Cells; Idiopathic Pulmonary Fibrosis; Imaging, Three-Dimensional; Male; Mice, Inbred C57BL; X-Ray Microtomography; Mice
PubMed: 33406369
DOI: 10.1165/rcmb.2020-0542MA