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Nature Aug 2018The airways of the lung are the primary sites of disease in asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal...
The airways of the lung are the primary sites of disease in asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal epithelium by single-cell RNA-sequencing (scRNA-seq) and in vivo lineage tracing. We identify a rare cell type, the Foxi1 pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that we term 'hillocks'; and disease-relevant subsets of tuft and goblet cells. We developed 'pulse-seq', combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the cystic fibrosis transmembrane conductance regulator in both mouse (Cftr) and human (CFTR). Knockout of Foxi1 in mouse ionocytes causes loss of Cftr expression and disrupts airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease.
Topics: Animals; Asthma; Cell Differentiation; Cell Lineage; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Female; Forkhead Transcription Factors; Gene Expression Profiling; Gene Expression Regulation; Goblet Cells; Humans; Lung; Male; Mice; Sequence Analysis, RNA; Single-Cell Analysis; Trachea
PubMed: 30069044
DOI: 10.1038/s41586-018-0393-7 -
Experimental and Therapeutic Medicine Oct 2020Ocular cicatricial pemphigoid is a particular form of mucous membrane pemphigoid and it is characterized by a chronic bilateral conjunctivitis with relapsing-remitting... (Review)
Review
Ocular cicatricial pemphigoid is a particular form of mucous membrane pemphigoid and it is characterized by a chronic bilateral conjunctivitis with relapsing-remitting periods. Without therapy 75% of the cases develop visual loss due to major ocular complications (e.g. severe dry-eye syndrome, corneal erosions, corneal keratinization, entropion, symblepharon). Pathogenesis remains uncertain and probably linked to an autoimmune type II hypersensitivity response in patients with a genetic predisposition and exposure to different environmental triggers. With a worldwide distribution, no racial predilection and an estimated incidence that largely varies from 1/10,000-1/60,000, ocular cicatricial pemphigoid predominantly affects women aged ~60 years. Conjunctival biopsy with direct immunofluorescence is the gold standard in diagnosis confirmation, but up to 40% of the patients have a negative biopsy result that does not rule out the diagnosis. The skin and many other mucous membranes (e.g. oral, trachea, esophagus, pharynx, larynx, urethra, vagina and anus) may be involved. The disease grading relies on Foster staging system (based on clinical signs) and Mondino and Brown system (based on the inferior fornix depth loss). The differential diagnosis includes atopy, allergies, trauma, chemical burns, radiation, neoplasia, infectious, inflammatory and autoimmune etiologies. The main goals of the treatment are to stop disease progression, to relieve symptoms and to prevent complications. With long-term systemic therapy 90% of the cases can be efficiently controlled. While Dapsone is the first-line treatment in mild to moderate disease in patients without G6PD deficiency, more severe cases require immunosuppressant therapy with azathioprine, mycophenolate mofetil, methotrexate or cyclosporine. Cyclophosphamide, biologics (etanercept or rituximab) and intravenous immunoglobulin therapy are usually reserved for recalcitrant disease and unsatisfactory results to conventional therapy. Dry eye syndrome requires constant lubricating medication and topical steroids, cyclosporine-A and tacrolimus. Surgery should be planed only in quiescent phase as minor conjunctival trauma can significantly worsen the disease.
PubMed: 32905166
DOI: 10.3892/etm.2020.8972 -
Development (Cambridge, England) Oct 2019The upper airway epithelium, which is mainly composed of multiciliated, goblet, club and basal cells, ensures proper mucociliary function and can regenerate in response...
The upper airway epithelium, which is mainly composed of multiciliated, goblet, club and basal cells, ensures proper mucociliary function and can regenerate in response to assaults. In chronic airway diseases, defective repair leads to tissue remodeling. Delineating key drivers of differentiation dynamics can help understand how normal or pathological regeneration occurs. Using single-cell transcriptomics and lineage inference, we have unraveled trajectories from basal to luminal cells, providing novel markers for specific populations. We report that: (1) a precursor subgroup of multiciliated cells, which we have entitled deuterosomal cells, is defined by specific markers, such as DEUP1, FOXN4, YPEL1, HES6 and CDC20B; (2) goblet cells can be precursors of multiciliated cells, thus explaining the presence of hybrid cells that co-express markers of goblet and multiciliated cells; and (3) a repertoire of molecules involved in the regeneration process, such as keratins or components of the Notch, Wnt or BMP/TGFβ pathways, can be identified. Confirmation of our results on fresh human and pig airway samples, and on mouse tracheal cells, extend and confirm our conclusions regarding the molecular and cellular choreography at work during mucociliary epithelial differentiation.
Topics: Animals; Cell Differentiation; Cells, Cultured; Epithelial Cells; Goblet Cells; Humans; Mice; RNA-Seq; Respiratory Mucosa; Swine; Trachea
PubMed: 31558434
DOI: 10.1242/dev.177428 -
Immunity Jul 2018In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the...
In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis and a tritrichomonad protist both secreted succinate as a metabolite. In vivo sensing of the tritrichomonad required SUCNR1, whereas N. brasiliensis was SUCNR1 independent. These findings define a paradigm wherein tuft cells monitor microbial metabolites to initiate type 2 immunity and suggest the existence of other sensing pathways triggering the response to helminths.
Topics: Animals; Cell Line; Female; Immunity, Mucosal; Intestinal Mucosa; Intestine, Small; Male; Mice, Inbred C57BL; Mice, Knockout; Nippostrongylus; Organ Specificity; Protozoan Infections; Receptors, G-Protein-Coupled; Signal Transduction; Species Specificity; Strongylida Infections; Succinic Acid; TRPM Cation Channels; Th2 Cells; Tritrichomonas
PubMed: 30021144
DOI: 10.1016/j.immuni.2018.06.016 -
Case Reports in Otolaryngology 2021Upper airway granulomas are commonly encountered benign masses and are a result of pronounced tissue reactivity to localized respiratory mucosal trauma. The mechanism of...
BACKGROUND
Upper airway granulomas are commonly encountered benign masses and are a result of pronounced tissue reactivity to localized respiratory mucosal trauma. The mechanism of injury to respiratory epithelium is most commonly iatrogenic and associated with intubation or indwelling tracheostomy. . A 40-year-old obese female with a history of multiple intubations, poorly controlled diabetes mellitus type II, and history of tracheal stenosis presented with sudden onset respiratory distress requiring intubation at an outside hospital. Direct laryngoscopy revealed a rapidly forming transglottic tissue mass, measuring 5.0 × 2.2 × 0.8 cm. The following case represents an unusual exception to our experience with granulomas given its rapidity of onset and migration of tissue around the endotracheal tube. Discussion. Laryngeal erythema and granulation formation are expected postintubation findings in most patients; however, the large size of granuloma tissue and rapid onset of symptoms in this case make it remarkable. Our patient had multiple risk factors for postintubation stenosis: female sex, poorly controlled diabetes, hypertension, obesity, and multiple prior intubations for periods lasting longer than forty-eight hours.
CONCLUSION
Our case highlights a rare laryngeal finding of a large granulation tissue mass causing sudden onset airway obstruction.
PubMed: 33688444
DOI: 10.1155/2021/6697478 -
Nature Feb 2022It is not fully understood why COVID-19 is typically milder in children. Here, to examine the differences between children and adults in their response to SARS-CoV-2... (Comparative Study)
Comparative Study
It is not fully understood why COVID-19 is typically milder in children. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.
Topics: Adult; Bronchi; COVID-19; Chicago; Cohort Studies; Dendritic Cells; Disease Progression; Epithelial Cells; Female; Humans; Immunity, Innate; Interferons; Killer Cells, Natural; London; Male; Nasal Mucosa; SARS-CoV-2; Single-Cell Analysis; T-Lymphocytes, Cytotoxic; Trachea; Young Adult
PubMed: 34937051
DOI: 10.1038/s41586-021-04345-x -
Nature Cell Biology May 2021Coordination of stem cell function by local and niche-derived signals is essential to preserve adult tissue homeostasis and organismal health. The vasculature is a...
Coordination of stem cell function by local and niche-derived signals is essential to preserve adult tissue homeostasis and organismal health. The vasculature is a prominent component of multiple stem cell niches. However, its role in adult intestinal homeostasis remains largely understudied. Here we uncover a previously unrecognised crosstalk between adult intestinal stem cells in Drosophila and the vasculature-like tracheal system, which is essential for intestinal regeneration. Following damage to the intestinal epithelium, gut-derived reactive oxygen species activate tracheal HIF-1α and bidirectional FGF/FGFR signalling, leading to reversible remodelling of gut-associated terminal tracheal cells and intestinal stem cell proliferation following damage. Unexpectedly, reactive oxygen species-induced adult tracheal plasticity involves downregulation of the tracheal specification factor trachealess (trh) and upregulation of IGF2 messenger RNA-binding protein (IGF2BP2/Imp). Our results reveal an intestine-vasculature inter-organ communication programme that is essential to adapt the stem cell response to the proliferative demands of the intestinal epithelium.
Topics: Adaptation, Physiological; Adult Stem Cells; Animals; Drosophila; Homeostasis; Intestinal Mucosa; RNA-Binding Proteins; Regeneration; Signal Transduction; Stem Cell Niche; Stem Cells
PubMed: 33972729
DOI: 10.1038/s41556-021-00676-z -
Annals of Cardiothoracic Surgery Mar 2018Laryngotracheal trauma is a rare but potentially life-threatening injury. It is usually seen in multiple-trauma patients and can go unrecognized and undertreated due to... (Review)
Review
Laryngotracheal trauma is a rare but potentially life-threatening injury. It is usually seen in multiple-trauma patients and can go unrecognized and undertreated due to its scarcity. The presenting symptoms often do not correlate with the severity of the injury and injuries may range from an endolaryngeal hematoma to a complete tracheal transection. Accurate diagnosis of the extent of the injury can be achieved with a combination of high resolution computed tomography, flexible fiber optic laryngoscopy and flexible bronchoscopy. Treatment may include observation with symptomatic management, reduction and repair of laryngeal skeletal fractures, or complete tracheal or laryngeal reconstruction. Endolaryngeal stents are reserved for use in cases of significant mucosal trauma or injuries that disrupt the anterior commissure of the larynx. The most important goal in management is to first secure and reconstruct the airway. Once this has been achieved, the long-term goal of treatment is to restore the voice and swallowing mechanism.
PubMed: 29707498
DOI: 10.21037/acs.2018.03.03 -
European Annals of Otorhinolaryngology,... Feb 2016Tracheal rhinoscleroma is an infectious granulomatosis of the tracheobronchial tract caused by a Gram-negative bacillus. Exclusively tracheal involvement has been rarely...
INTRODUCTION
Tracheal rhinoscleroma is an infectious granulomatosis of the tracheobronchial tract caused by a Gram-negative bacillus. Exclusively tracheal involvement has been rarely reported in the literature. The purpose of this study was to report a case of subglottic stenosis secondary to rhinoscleroma.
SUMMARY
A 46-year-old North African woman with no medical or surgical history presented with inspiratory dyspnoea that had been present for several years. Endoscopic examination under general anaesthesia revealed tracheal stenosis. Histological examination of mucosal biopsies demonstrated Mikulicz cells and culture of bacteriological samples taken during a second biopsy confirmed the diagnosis of rhinoscleroma. CO2 laser subglottic obstruction relief was performed and treatment with ofloxacin was initiated. No recurrence of tracheal stenosis was observed with a follow-up of 6 months.
DISCUSSION
The diagnosis of rhinoscleroma is based on histological and bacteriological examination. Cultures are positive in 60% of cases, but negative cultures do not exclude the diagnosis of rhinoscleroma. Specific treatment consists of long-term antibiotic therapy, while surgery may be indicated for symptomatic treatment.
Topics: Anti-Bacterial Agents; Dyspnea; Female; Humans; Laser Therapy; Middle Aged; Ofloxacin; Rhinoscleroma; Tracheal Diseases; Tracheal Stenosis
PubMed: 26769262
DOI: 10.1016/j.anorl.2015.03.009