Every breath passes over a living lining that is made of many kinds of cells, each with its own job. In the airways, most of these cells cooperate to trap dirt and germs and sweep them out. Deep in the lungs, a different pair of cells takes over the work of moving oxygen into the blood. One of the most important members of the team, a rare cell that carries the cystic fibrosis gene, was only discovered in 2018.
Ciliated Cells Sweep the Airways Clean
Each ciliated cell is covered in hair-like cilia, and each cilium is a tiny motor. Its core is a ring of nine paired protein tubes surrounding a central pair.1PubMed Central. Airway Epithelial Cell Cilia and Obstructive Lung Disease Small arms on those tubes use the cell’s energy supply to bend the cilium back and forth.2PubMed Central. Airway Epithelial Cell Cilia and Obstructive Lung Disease Faults in different parts of this machinery cause different problems, from stiff cilia to slow beating to cilia that spin in circles instead of sweeping.3PubMed Central. Airway Epithelial Cell Cilia and Obstructive Lung Disease When cilia beat badly, mucus sits in the airways instead of moving out.
The beat itself is organised. Each stroke has a fast, stiff power stroke that pushes mucus forward, followed by a slower, bent recovery stroke that brings the cilium back with less drag on the mucus. Neighbouring cilia beat slightly out of step with one another, producing travelling waves like wind across a wheat field, which moves mucus more smoothly than everything beating at once. Because every cell is oriented the same way, the combined push is aimed toward the throat rather than cancelling out.
Mucus traps inhaled particles, and cilia push it upward. It runs continuously, day and night, with no conscious effort. Ciliated cells are the motor, and the mucus-making cells in the next section supply the belt, which is why it is often called the mucus escalator.
Mucus from the small airways joins larger flows as it climbs, so the stream gathers volume as it nears the windpipe. At the top it reaches the throat, where it is usually swallowed without you noticing, and stomach acid deals with the trapped material. You notice it only when there is more than usual, such as when you need to clear your throat during a cold, or when it is coughed up.
Cilia also respond to touch. In airway cells grown in the lab, touching the cell surface made cilia beat at least 20% faster for a short time.4PubMed Central. Mechanosensitivity of cultured ciliated cells from the mammalian respiratory tract: implications for the regulation of mucociliary transport The speed-up spread to neighbouring cells in every direction.5PubMed Central. Mechanosensitivity of cultured ciliated cells from the mammalian respiratory tract: implications for the regulation of mucociliary transport It only happened when calcium was present outside the cells.6PubMed Central. Mechanosensitivity of cultured ciliated cells from the mammalian respiratory tract: implications for the regulation of mucociliary transport Clearing therefore appears to be a local, self-adjusting system that responds where mucus builds up.7PubMed Central. Mechanosensitivity of cultured ciliated cells from the mammalian respiratory tract: implications for the regulation of mucociliary transport
When the escalator fails, mucus pools and becomes a place where bacteria can grow, and people rely more on coughing to clear their airways. Inherited cilia defects lead to repeated chest and sinus infections from childhood.
Goblet Cells and Glands Make the Mucus
Goblet cells on the airway surface mainly produce a mucus protein called MUC5AC.8PubMed Central. Different mucins are produced by the surface epithelium and the submucosa in human trachea: identification of MUC5AC as a major mucin from the goblet cells Glands tucked under the lining make mostly a different one, MUC5B.9PubMed. Expression of MUC5AC and MUC5B mucins in normal and cystic fibrosis lung The glands lie mostly in the larger airways, and narrow ducts carry their mucus and fluid up to the surface, where it joins the mucus from goblet cells.
The glands do more than make mucus. Their mucous cells make mucins, while their serous cells make germ-fighting proteins and watery fluid.10PubMed Central. Cellular and molecular architecture of submucosal glands in wild-type and cystic fibrosis pigs That fluid includes lysozyme, which breaks down bacteria, and a protein that starves bacteria of iron.11PubMed. Regulation of antiprotease and antimicrobial protein secretion by airway submucosal gland serous cells
Mucins are very large proteins heavily coated with sugars, and they hold water. They link together into long, tangled strands, and this network turns a watery secretion into a gel. MUC5AC and MUC5B differ in how the gel is built and how it behaves, which is why the type matters and not just the amount. The layer on the surface has two parts. A thin watery layer lets cilia beat freely, and a thicker gel sits on top and catches particles.
The balance between the two shows up clearly in disease. MUC5B is needed for mucus to be cleared properly, while MUC5AC does not help clearing.12PubMed Central. Expression Levels of MUC5AC and MUC5B in Airway Goblet Cells Are Associated with Traits of COPD and Progression of Chronic Airflow Limitation Mice lacking MUC5B develop plugged airways and more infections.13PubMed Central. Expression Levels of MUC5AC and MUC5B in Airway Goblet Cells Are Associated with Traits of COPD and Progression of Chronic Airflow Limitation Too much MUC5AC is linked to asthma, cystic fibrosis and COPD.14PubMed Central. Expression Levels of MUC5AC and MUC5B in Airway Goblet Cells Are Associated with Traits of COPD and Progression of Chronic Airflow Limitation In people, high MUC5AC with low MUC5B went along with smoking, chronic bronchitis and emphysema.15PubMed Central. Expression Levels of MUC5AC and MUC5B in Airway Goblet Cells Are Associated with Traits of COPD and Progression of Chronic Airflow Limitation
Trouble comes from the wrong kind of mucus or too much of it, since thick, sticky mucus is harder for cilia to move. That is why researchers now aim to rebalance specific mucins rather than block mucus entirely.
Ionocytes and the Cystic Fibrosis Gene
Ionocytes are a rare airway cell type identified in 2018.16PubMed Central. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte They carry the highest levels of CFTR, the cystic fibrosis gene, of any airway lining cell.17PubMed Central. Cystic Fibrosis and the Cells of the Airway Epithelium: What Are Ionocytes and What Do Did They Do? That makes them a major source of CFTR activity in the airways, even though they are few.18PubMed Central. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte CFTR controls the flow of salt and water that keeps mucus runny.
Losing ionocytes disrupted airway fluid and mucus in ways seen in cystic fibrosis.19PubMed Central. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes In mice without ionocytes, mucus appeared thicker even though the depth of the surface fluid did not change.20PubMed Central. Cystic Fibrosis and the Cells of the Airway Epithelium: What Are Ionocytes and What Do Did They Do?
This changed how people think about cystic fibrosis. Before 2018, CFTR was thought to work mainly in the common ciliated cells, and those cells do still carry it. Now attention turns to a small population of cells, and gene therapies may need to reach ionocytes, not just any airway cell. Serous gland cells also carry CFTR, so the glands are involved too.21PubMed. Regulation of antiprotease and antimicrobial protein secretion by airway submucosal gland serous cells In cystic fibrosis, thick mucus that cilia cannot move plugs airways and traps bacteria, and lung infections become repeated and long-lasting.
Sensor Cells That Watch the Air
Neuroendocrine cells share features of nerve cells and hormone-releasing cells, which lets them sense something and then release chemical messengers. They are scattered through the airway lining, and some sit in clusters close to nerve endings. These cells detect low oxygen.22PubMed Central. Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease When oxygen drops they release serotonin, which narrows lung blood vessels.23PubMed Central. Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease They also release CGRP, which widens vessels and improves lung circulation.24PubMed Central. Pulmonary neuroendocrine cells: crucial players in respiratory function and airway-nerve communication Together this helps match blood flow to where air is reaching in the lungs.25PubMed Central. Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease They also help adjust breathing rate and detect pollutants and allergens.26PubMed Central. Pulmonary neuroendocrine cells: crucial players in respiratory function and airway-nerve communication
The narrowing makes sense once you consider a poorly aired part of the lung. Sending blood there wastes it, since the blood cannot pick up much oxygen. Narrowing the vessels in that area pushes blood toward better-ventilated regions, which keeps the oxygen reaching the body as high as possible even when the lung is uneven.
Tuft cells work more like taste buds. They carry the same bitter-taste sensors found on the tongue.27PubMed Central. Cholinergic chemosensory cells in the trachea regulate breathing In mice, these cells signal nerves that alter breathing.28PubMed Central. Cholinergic chemosensory cells in the trachea regulate breathing In human windpipe tissue, bitter substances sped up the mucus escalator through tuft-cell signals.29PubMed Central. Human airway tuft cells influence the mucociliary clearance through cholinergic signalling Many harmful bacteria and chemicals release bitter compounds, so detecting them early lets the airway step up clearing before damage is done.
Alveolar Cells Handle Gas Exchange
Deep in the lungs there are no cilia and no mucus, since mucus would block gas exchange. Cleaning here relies on immune cells instead. Two cell types line the air sacs.
Type I cells are spread into extremely thin plates with almost nothing inside.30PubMed. Alveolar type I and type II cells Oxygen and carbon dioxide can cross them quickly.31PubMed. Alveolar type I and type II cells Gas moves by diffusion, and the shorter the distance, the faster it crosses. These cells cover about 95% of the air-sac surface,32PubMed Central. Activation of type II cells into regenerative stem cell antigen-1(+) cells during alveolar repair and damage to them quickly affects oxygen levels. They are fragile and easily harmed by infection or toxins.
Type II cells make surfactant, a fatty liquid coating.33PubMed. Biology of alveolar type II cells Surfactant stops the tiny air sacs collapsing when you breathe out.34Molecular Biology and Evolution. Highlight: comparative single-cell analysis reveals how birds and mammals build distinct lung architectures This is why premature babies, who lack surfactant, struggle to breathe. Type II cells also repair the sacs: after injury they multiply and turn into new type I cells.35PubMed Central. Activation of type II cells into regenerative stem cell antigen-1(+) cells during alveolar repair During repair, cells pass through an in-between stage on the way.36PubMed Central. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis In lung fibrosis, cells can stall in this in-between stage.37PubMed Central. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis When repair stalls, scar tissue builds instead of new thin cells, so the lungs become stiff and oxygen levels fall.
Basal and Club Cells Rebuild the Lining
Basal cells sit at the bottom of the lining, anchored to its base.38Nature / Mucosal Immunology. Cellular and functional heterogeneity of the airway epithelium They make up roughly 6 to 31% of airway lining cells, depending on how deep in the airway.39Nature / Mucosal Immunology. Cellular and functional heterogeneity of the airway epithelium They can turn into almost every other airway cell type, including ciliated cells, mucus-making cells and ionocytes.40PubMed Central. Roles of airway basal stem cells in lung homeostasis and regenerative medicine That is what makes them stem cells: they can renew themselves and also produce more specialised cells, so they keep a reserve of themselves while supplying the others. Their position at the base protects them while the surface cells take the damage.
In healthy airways they stay mostly quiet and switch on after injury.41PubMed Central. Airway basal stem cell therapy for lung diseases: an emerging regenerative medicine strategy After damage from smoke, infection or inherited disease they multiply to restore the lining.42PubMed Central. Airway basal stem cell therapy for lung diseases: an emerging regenerative medicine strategy Researchers hope to use basal cells as therapy for lung disease.43PubMed Central. Airway basal stem cell therapy for lung diseases: an emerging regenerative medicine strategy After a bad cold, the lining is rebuilt over weeks, and a lingering cough after infection can reflect lining that is still recovering.
Club cells line the smallest airways.44PubMed Central. An update in club cell biology and its potential relevance to chronic obstructive pulmonary disease They help defend against germs, break down inhaled chemicals and repair injury.45PubMed Central. An update in club cell biology and its potential relevance to chronic obstructive pulmonary disease
How Smoking, COPD and Flu Change These Cells
Cigarette smoke disrupts how basal cells mature into working cells.46PubMed Central. Cigarette smoke alters primary human bronchial epithelial cell differentiation at the air-liquid interface The lining gains extra goblet cells and forms flat, skin-like patches.47PubMed Central. Cigarette smoke alters primary human bronchial epithelial cell differentiation at the air-liquid interface In smokers with COPD, about 10 to 17% of the airway lining had these flat patches, while healthy non-smokers had none.48PubMed Central. Squamous Metaplasia Is Increased in the Bronchial Epithelium of Smokers with Chronic Obstructive Pulmonary Disease
Smoke injures the lining repeatedly, so basal cells are called on again and again. With maturation disrupted, they make extra goblet cells and flat patches in place of ciliated cells, leaving more mucus and a weaker escalator. The flat patches can withstand some injury, but they do not make mucus or carry cilia, so they add no clearing power.
Removing smoke stops the ongoing injury, and basal cells can resume normal repair. Coughing may increase early on as cilia recover. Quitting is the most effective step to protect these cells.
Flu viruses attach to sugar receptors on airway cells.49PubMed Central. Influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells Human flu strains mainly infect ciliated cells.50PubMed Central. Tropism and infectivity of influenza virus, including highly pathogenic avian H5N1 virus, in ferret tracheal differentiated primary epithelial cell cultures Bird flu receptors are found deeper, including on type II air sac cells,51PubMed Central. Influenza virus receptor specificity and cell tropism in mouse and human airway epithelial cells so bird flu can reach deep into the lung, which may help explain severe illness.
Flu also explains the cough that lingers. Infected ciliated cells die and are shed, and the escalator slows until new cells grow. Meanwhile, mucus must be coughed out.