Alveoli are first located in therespiratory bronchioles that mark the beginning of therespiratory zone. They are located sparsely in these bronchioles, line the walls of thealveolar ducts, and are more numerous in the blind-endedalveolar sacs.[5] Theacini are the basic units of respiration, withgas exchange taking place in all the alveoli present.[6] The alveolar membrane is the gas exchange surface, surrounded by a network ofcapillaries. Oxygen isdiffused across the membrane into the capillaries and carbon dioxide is released from the capillaries into the alveoli to be breathed out.[7][8]
Alveoli are particular to mammalian lungs. Different structures are involved in gas exchange in other vertebrates.[9]
The alveoli are first located in the respiratory bronchioles as scattered outpockets, extending from their lumens. The respiratory bronchioles run for considerable lengths and become increasingly alveolated with side branches ofalveolar ducts that become deeply lined with alveoli. The ducts number between two and eleven from each bronchiole.[10] Each duct opens into five or sixalveolar sacs into which clusters of alveoli open.
Each terminal respiratory unit is called anacinus and consists of the respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli. New alveoli continue to form until the age of eight years.[5]
A typical pair ofhuman lungs contains about 480 million alveoli,[11] providing a total surface area for gas exchange of between 70 and 80 square metres.[10] Each alveolus is wrapped in a fine mesh ofcapillaries covering about 70% of its area.[12] The diameter of an alveolus is between 200 and 500μm.[12]
An alveolus consists of anepithelial layer of simplesquamous epithelium (very thin, flattened cells),[13] and anextracellular matrix surrounded bycapillaries. The epithelial lining is part of the alveolar membrane, also known as the respiratory membrane, that allows theexchange of gases. The membrane has several layers – a layer ofalveolar lining fluid that containssurfactant, the epithelial layer and its basement membrane; a thininterstitial space between the epithelial lining and the capillary membrane; a capillary basement membrane that often fuses with the alveolar basement membrane, and the capillaryendothelial membrane. The whole membrane however is only between 0.2μm at its thinnest part and 0.6 μm at its thickest.[14]
In thealveolar walls there are interconnecting air passages between the alveoli known as thepores of Kohn. Thealveolar septum that separates the alveoli in the alveolar sac contains somecollagen fibers andelastic fibers. The septa also house the enmeshed capillary network that surrounds each alveolus.[3] The elastic fibres allow the alveoli to stretch when they fill with air during inhalation. They then spring back during exhalation in order to expel the carbon dioxide-rich air.
A histologic slide of a human alveolar sac
There are three major types ofalveolar cell. Two types arepneumocytes orpneumonocytes known as type I and type II cells found in the alveolar wall, and a largephagocytic cell known as analveolar macrophage that moves about in the lumens of the alveoli, and in the connective tissue between them. Type I cells, also called type I pneumocytes, or type I alveolar cells, are squamous, thin and flat and form the structure of the alveoli. Type II cells, also called type II pneumocytes or type II alveolar cells, releasepulmonary surfactant to lowersurface tension, and can alsodifferentiate to replace damaged type I cells.[12][15]
Development of the earliest structures that will contain alveoli begins on day 22 and is divided into five stages: embryonic, pseudoglandular, canalicular, saccular, and alveolar stage.[16] The alveolar stage begins approximately 36 weeks into development. Immature alveoli appear as bulges from the sacculi which invade the primary septa. As the sacculi develop, the protrusions in the primary septa become larger; new septations are longer and thinner and are known as secondary septa.[16] Secondary septa are responsible for the final division of the sacculi into alveoli. Majority of alveolar division occurs within the first 6 months but continue to develop until 3 years of age. To create a thinner diffusion barrier, the double-layer capillary network fuse into one network, each one closely associated with two alveoli as they develop.[16]
In the first three years of life, the enlargement of lungs is a consequence of the increasing number of alveoli; after this point, both the number and size of alveoli increases until the development of lungs finishes at approximately 8 years of age.[16]
The cross section of an alveolus with capillaries is shown. Part of the cross section is magnified to show diffusion of oxygen gas and carbon dioxide through type I cells and capillary cells.Gas exchange in the alveolus
Type I cells are the larger of the two cell types; they are thin, flat epithelial lining cells (membranous pneumocytes), that form the structure of the alveoli.[3] They are squamous (giving more surface area to each cell) and have longcytoplasmic extensions that cover more than 95% of the alveolar surface.[12][17] A thin lining ofepithelium covers the alveoli, aiding thediffusion ofgas exchange between the air in the alveoli and theblood in the surrounding capillaries.
Type I cells are extremely thin, sometimes being only 25 nm thick; asvisible light has awavelength in hundreds of nanometres,electron microscopy is required to observe these cells.
Thenucleus of a type I cell occupies a large area of free cytoplasm and itsorganelles are clustered around it reducing the thickness of the cell. This also keeps the thickness of theblood-air barrier reduced to a minimum.
The cytoplasm in the thin portion containspinocytotic vesicles which may play a role in the removal of small particulate contaminants from the outer surface. In addition todesmosomes, all type I alveolar cells have occluding junctions that prevent the leakage of tissue fluid into the alveolar air space.
The relatively low solubility (and hence rate of diffusion) of oxygen necessitates the large internal surface area (about 80 square m [96 square yards]) and very thin walls of the alveoli. Weaving between the capillaries and helping to support them is anextracellular matrix, a meshlike fabric of elastic and collagenous fibres. The collagen fibres, being more rigid, give the wall firmness, while the elastic fibres permit expansion and contraction of the walls during breathing.
Type I pneumocytes are unable toreplicate and are susceptible to toxicinsults. In the event of damage, type II cells can proliferate and differentiate into type I cells to compensate.[18]
Type II cells are cuboidal and much smaller than type I cells.[3] They are the most numerous cells in the alveoli, yet do not cover as much surface area as the squamous type I cells.[18] Type II cells (granulous pneumocytes) in the alveolar wall contain secretoryorganelles known aslamellar bodies or lamellar granules, that fuse with the cell membranes and secretepulmonary surfactant. This surfactant is a film of fatty substances, a group ofphospholipids that reduce alveolarsurface tension. The phospholipids are stored in the lamellar bodies. Without this coating, the alveoli would collapse. The surfactant is continuously released byexocytosis. Reinflation of the alveoli following exhalation is made easier by the surfactant, which reduces surface tension in the thinfluid lining of the alveoli. The fluid coating is produced by the body in order to facilitate the transfer of gases between blood and alveolar air, and the type II cells are typically found at theblood–air barrier.[19][20]
Type II cells start to develop at about 26 weeks ofgestation, secreting small amounts of surfactant. However, adequate amounts of surfactant are not secreted until about 35 weeks of gestation – this is the main reason for increased rates ofinfant respiratory distress syndrome, which drastically reduces at ages above 35 weeks gestation.
Type II cells are also capable of cellular division, giving rise to more type I and II alveolar cells when the lung tissue is damaged.[21]
MUC1, a humangene associated with type II pneumocytes, has been identified as a marker inlung cancer.[22]
The importance of the type 2 lung alveolar cells in the development of severe respiratory symptoms of COVID-19 and potential mechanisms on how these cells are protected by the SSRIs fluvoxamine and fluoxetine was summarized in a review in April 2022.[23]
Thealveolar macrophages reside on the internal luminal surfaces of the alveoli, the alveolar ducts, and the bronchioles. They are mobile scavengers that serve to engulf foreign particles in the lungs, such as dust, bacteria, carbon particles, and blood cells from injuries.[24] They are also calledpulmonary macrophages, anddust cells. Alveolar macrophages also play a crucial role in immune responses against viral pathogens in the lungs.[25] They secrete cytokines and chemokines, which recruit and activate other immune cells, initiate type I interferon signaling, and inhibit the nuclear export of viral genomes.[25]
Impaired surfactant regulation can cause an accumulation of surfactant proteins to build up in the alveoli in a condition calledpulmonary alveolar proteinosis. This results in impaired gas exchange.[29]
Inasthma, thebronchioles become narrowed, causing the amount of air flow into the lung tissue to be greatly reduced. It can be triggered by irritants in the air,photochemical smog for example, as well as substances to which a person is allergic.
Chronic bronchitis occurs when anabundance of mucus is produced by the lungs. The production of mucus occurs naturally when the lung tissue is exposed to irritants. In chronic bronchitis, the air passages into the alveoli, the respiratory bronchioles, become clogged with mucus. This causes increased coughing in order to remove the mucus, and is often a result of extended periods of exposure to cigarette smoke.
Cryptococcosis of lung in patient with AIDS. Mucicarmine stain. Histopathology of lung shows widened alveolar septum containing a few inflammatory cells and numerous yeasts ofCryptococcus neoformans. The inner layer of the yeast capsule stain red.
Almost any type oflung tumor orlung cancer can compress the alveoli and reduce gas exchange capacity. In some cases the tumor will fill the alveoli.[33]
Cavitary pneumonia is a process in which the alveoli are destroyed and produce a cavity. As the alveoli are destroyed, the surface area for gas exchange to occur becomes reduced. Further changes in blood flow can lead to decline in lung function.
Emphysema is another disease of the lungs, whereby theelastin in the walls of the alveoli is broken down by an imbalance between the production ofneutrophil elastase (elevated by cigarette smoke) andalpha-1 antitrypsin (the activity varies due to genetics or reaction of a critical methionine residue with toxins including cigarette smoke). The resulting loss of elasticity in the lungs leads to prolonged times for exhalation, which occurs through passive recoil of the expanded lung. This leads to a smaller volume of gas exchanged per breath.
Several factors, including smoking, viral infections, and aging, contribute to physical damage to type II alveolar cells. Some studies have linked injury to these cells to the proliferation offibrosis in the lungs and the onset ofidiopathic pulmonary fibrosis.[34]
Apulmonary contusion is abruise of the lung tissue caused by trauma.[35] Damaged capillaries from a contusion can cause blood and other fluids to accumulate in the tissue of the lung, impairing gas exchange.
Pulmonary edema is the buildup of fluid in the parenchyma and alveoli. An edema is usually caused by left ventricular heart failure, or by damage to the lung or its vasculature.
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^abcdStanton, Bruce M.; Koeppen, Bruce A., eds. (2008). Berne & Levy physiology (6th ed.). Philadelphia: Mosby/Elsevier. pp. 418–422.ISBN978-0-323-04582-7.
^"Bronchi, Bronchial Tree & Lungs".SEER Training Modules. U.S. Department of Health and Human Services National Institutes of Health National Cancer Institute.
^Hall J (2011).Guyton and Hall Textbook of Medical Physiology. Saunders Elsevier. pp. 489–491.ISBN978-1-4160-4574-8.
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