A Single-Cell Atlas of the Human Healthy Airways

American Journal of Respiratory and Critical Care Medicine, Год журнала: 2020, Номер 202(12), С. 1636 - 1645

Опубликована: Июль 29, 2020

Rationale: The respiratory tract constitutes an elaborate line of defense that is based on a unique cellular ecosystem.Objectives: We aimed to investigate cell population distributions and transcriptional changes along the airways by using single-cell RNA profiling.Methods: have explored heterogeneity human airway epithelium in 10 healthy living volunteers profiling. A total 77,969 cells were collected at 35 distinct locations, from nose 12th division tree.Measurements Main Results: resulting atlas composed high percentage epithelial (89.1%) but also immune (6.2%) stromal (4.7%) with proportions different regions airways. It reveals differential gene expression between identical types (suprabasal, secretory, multiciliated cells) (MUC4, PI3, SIX3) tracheobronchial (SCGB1A1, TFF3) By contrast, cell-type-specific stable across all samples. Our improves description ionocytes, pulmonary neuroendocrine cells, brush identifies related NREP-positive cells. report association KRT13 dividing are reminiscent previously described mouse "hillock" squamous expressing SCEL SPRR1A/B.Conclusions: Robust characterization cohort establishes valuable resource for future investigations. precise continuum existing nasal successive divisions profile these better defines conditions under which relevant proxies diseases can be developed.

Язык: Английский

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Role of CFTR in epithelial physiology

Cellular and Molecular Life Sciences, Год журнала: 2016, Номер 74(1), С. 93 - 115

Опубликована: Окт. 6, 2016

Salt and fluid absorption secretion are two processes that fundamental to epithelial function whole body homeostasis, as such tightly regulated in tissues. The CFTR anion channel plays a major role regulating both diverse range of tissues, including the airways, GI reproductive tracts, sweat salivary glands. It is not surprising then defects linked disease, life-threatening secretory diarrhoeas, cholera, well inherited cystic fibrosis (CF), one most common life-limiting genetic diseases Caucasian populations. More recently, dysfunction has also been implicated pathogenesis acute pancreatitis, chronic obstructive pulmonary disease (COPD), hyper-responsiveness asthma, underscoring its health disease. regulates many mechanisms physiology, maintaining surface hydration luminal pH. Indeed, recent studies have identified pH an important arbiter barrier innate defence, particularly airways tract. In this chapter, we will illustrate different operational roles by describing characteristics three tissues: pancreas, gland.

Язык: Английский

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Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

BMC Pulmonary Medicine, Год журнала: 2016, Номер 16(1)

Опубликована: Дек. 1, 2016

The airways of patients with cystic fibrosis (CF) are highly complex, subject to various environmental conditions as well a distinct microbiota. Pseudomonas aeruginosa is recognized one the most important pulmonary pathogens and predominant cause morbidity mortality in CF. A multifarious interplay between host, pathogens, microbiota, environment shapes course disease. There have been several excellent reviews detailing CF pathology, role but only few connect these entities regards influence on overall holistic understanding contributing factors pertinent inform new research therapeutics.In this article, we discuss deterministic alterations lung physiology result We also revisit impact those changes special emphasis P. other non-genetic Substantial past current genetic aspects has reviewed assess effect different infection. thorough review indicate that infection multi-factorial no isolated should be solely targeted control disease progression. combinatorial approach may required ensure better outcomes.CF complex requires broad multidisciplinary improve outcomes. underlying mechanisms central development therapeutic strategies.

Язык: Английский

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Muco-Obstructive Lung Diseases

New England Journal of Medicine, Год журнала: 2019, Номер 380(20), С. 1941 - 1953

Опубликована: Май 15, 2019

This review covers the normal mechanisms of mucus formation and how they are abnormal in common conditions — such as COPD, cystic fibrosis, non–cystic fibrosis bronchiectasis that characterized by excessive airways.

Язык: Английский

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The role of mucus on drug transport and its potential to affect therapeutic outcomes

Advanced Drug Delivery Reviews, Год журнала: 2017, Номер 124, С. 82 - 97

Опубликована: Окт. 26, 2017

Язык: Английский

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Airway Epithelial Differentiation and Mucociliary Clearance

Annals of the American Thoracic Society, Год журнала: 2018, Номер 15(Supplement_3), С. S143 - S148

Опубликована: Ноя. 1, 2018

The lung is continuously exposed to particles, toxicants, and microbial pathogens that are cleared by a complex mechanical, innate, acquired immune system. Mucociliary clearance, mediated the actions of diverse conducting airway submucosal gland epithelial cells, plays critical role in multilayered defense system secreting fluids, electrolytes, antimicrobial antiinflammatory proteins, mucus onto surfaces. mucociliary escalator removes particles mechanical cilia cough. Abnormalities whether related impaired fluid secretion, ciliary dysfunction, lack cough, or disruption cells lining respiratory tract, contribute pathogenesis common chronic pulmonary disorders. Although other secretions play protecting during acute injury, clearance after hyperproduction causes obstruction infection, which morbidity disorders, including obstructive disease, asthma, idiopathic fibrosis, cystic bronchiectasis, primary dyskinesia. In this summary, molecular cellular mechanisms mediating as well goblet cell metaplasia hyperproduction, diseases considered.

Язык: Английский

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Inflammation in cystic fibrosis: An update

Pediatric Pulmonology, Год журнала: 2018, Номер 53(S3)

Опубликована: Июль 12, 2018

Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research important therapeutic target. In this review, we explore the most recent on major contributors to exuberant inflammatory response seen CF as well potential therapeutics combat response. Absence functional transmembrane conductance regulator (CFTR) alters anion transport across airway epithelial cells ultimately results dehydration surface liquid. The dehydrated liquid combination with abnormal mucin secretion contributes obstruction subsequent infection that may serve trigger point for inflammation. There is also evidence suggest inflammation be excessive sustained relative infectious stimuli. Studies have shown dysregulation both pro-inflammatory mediators such IL-17 pro-resolution including metabolites eicosanoid pathway. Recently, CFTR potentiators correctors garnered much attention community. Although these modulators address underlying defect CF, their impact downstream consequences are not known. Here, review pre-clinical clinical data addition, examine other cell types neutrophils, macrophages, T-lymphocytes express contribute Finally, challenges developing anti-inflammatory therapies highlight some promising drugs under development CF.

Язык: Английский

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Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications

American Journal of Respiratory and Critical Care Medicine, Год журнала: 2019, Номер 201(10), С. 1193 - 1208

Опубликована: Дек. 20, 2019

Section:ChooseTop of pageAbstract <

Язык: Английский

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Physiology and pathophysiology of human airway mucus

Physiological Reviews, Год журнала: 2022, Номер 102(4), С. 1757 - 1836

Опубликована: Янв. 10, 2022

The mucus clearance system is the dominant mechanical host defense of human lung. Mucus cleared from lung by cilia and airflow, including both two-phase gas-liquid pumping cough-dependent mechanisms, transport rates are heavily dependent on concentration. Importantly, accurately predicted gel-on-brush model mucociliary apparatus relative osmotic moduli periciliary-glycocalyceal (PCL-G) layers. fluid available to hydrate generated transepithelial transport. Feedback interactions between concentrations beating, via purinergic signaling, coordinate Na+ absorptive vs Cl- secretory maintain hydration in health. In disease, becomes hyperconcentrated (dehydrated). Multiple mechanisms derange ion pathways that normally muco-obstructive diseases, e.g., cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFB), primary ciliary dyskinesia (PCD). A key step pathogenesis compression layer onto airway surface with formation adherent plaques plugs, particularly distal airways. create locally hypoxic conditions produce airflow obstruction, inflammation, infection, and, ultimately, wall damage. Therapies clear hydrating mucolytic agents rational, strategies develop these reviewed.

Язык: Английский

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Building and Regenerating the Lung Cell by Cell

Physiological Reviews, Год журнала: 2018, Номер 99(1), С. 513 - 554

Опубликована: Ноя. 14, 2018

The unique architecture of the mammalian lung is required for adaptation to air breathing at birth and thereafter. Understanding cellular molecular mechanisms controlling its morphogenesis provides framework understanding pathogenesis acute chronic diseases. Recent single-cell RNA sequencing data high-resolution imaging identify remarkable heterogeneity pulmonary cell types selective gene expression underlying development. We will address fundamental issues related diversity cells, formation function lung, review recent advances regarding pathways involved in organogenesis. What cells form early embryo? How are proliferation, migration, differentiation regulated during morphogenesis? do interact repair? signaling transcriptional programs determine cell-cell interactions necessary function?

Язык: Английский

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