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Pulmonary alveolus
Pulmonary alveolus
Pulmonary alveolus
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Pulmonary alveolus
The alveoli
Details
SystemRespiratory system
LocationLung
Identifiers
Latinalveolus pulmonis
MeSHD011650
THH3.05.02.0.00026
FMA7318
Anatomical terminology

A pulmonary alveolus (pl. alveoli; from Latin alveolus 'little cavity'), also called an air sac or air space, is one of millions of hollow, distensible cup-shaped cavities in the lungs where pulmonary gas exchange takes place.[1] Oxygen is exchanged for carbon dioxide at the blood–air barrier between the alveolar air and the pulmonary capillary.[2] Alveoli make up the functional tissue of the mammalian lungs known as the lung parenchyma, which takes up 90 percent of the total lung volume.[3][4]

Alveoli are first located in the respiratory bronchioles that mark the beginning of the respiratory zone. They are located sparsely in these bronchioles, line the walls of the alveolar ducts, and are more numerous in the blind-ended alveolar sacs.[5] The acini are the basic units of respiration, with gas exchange taking place in all the alveoli present.[6] The alveolar membrane is the gas exchange surface, surrounded by a network of capillaries. Oxygen is diffused 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]

Structure

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Bronchial anatomy showing terminal bronchioles (BT) leading to respiratory bronchioles (BR) and alveolar ducts (DA) that open into alveolar sacs containing out pockets of alveoli (A) separated by alveolar septa (AS)

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 of alveolar ducts that become deeply lined with alveoli. The ducts number between two and eleven from each bronchiole.[10] Each duct opens into five or six alveolar sacs into which clusters of alveoli open.

Each terminal respiratory unit is called an acinus 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 of human 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 of capillaries covering about 70% of its area.[12] The diameter of an alveolus is between 200 and 500 μm.[12]

Microanatomy

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An alveolus consists of an epithelial layer of simple squamous epithelium (very thin, flattened cells),[13] and an extracellular matrix surrounded by capillaries. The epithelial lining is part of the alveolar membrane, also known as the respiratory membrane, that allows the exchange of gases. The membrane has several layers – a layer of alveolar lining fluid that contains surfactant, the epithelial layer and its basement membrane; a thin interstitial space between the epithelial lining and the capillary membrane; a capillary basement membrane that often fuses with the alveolar basement membrane, and the capillary endothelial membrane. The whole membrane however is only between 0.2 μm at its thinnest part and 0.6 μm at its thickest.[14]

In the alveolar walls there are interconnecting air passages between the alveoli known as the pores of Kohn. The alveolar septum that separates the alveoli in the alveolar sac contains some collagen fibers and elastic 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 of alveolar cell. Two types are pneumocytes or pneumonocytes known as type I and type II cells found in the alveolar wall, and a large phagocytic cell known as an alveolar 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, release pulmonary surfactant to lower surface tension, and can also differentiate to replace damaged type I cells.[12][15]

Development

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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]

Function

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An annotated diagram of the alveolus

Type I cells

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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 long cytoplasmic extensions that cover more than 95% of the alveolar surface.[12][17]

Type I cells are involved in the process of gas exchange between the alveoli and blood. These cells are extremely thin – sometimes only 25 nm – the electron microscope was needed to prove that all alveoli are lined with epithelium. This thin lining enables a fast diffusion of gas exchange between the air in the alveoli and the blood in the surrounding capillaries.

The nucleus of a type I cell occupies a large area of free cytoplasm and its organelles are clustered around it reducing the thickness of the cell. This also keeps the thickness of the blood-air barrier reduced to a minimum.

The cytoplasm in the thin portion contains pinocytotic vesicles which may play a role in the removal of small particulate contaminants from the outer surface. In addition to desmosomes, 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 an extracellular 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 to replicate and are susceptible to toxic insults. In the event of damage, type II cells can proliferate and differentiate into type I cells to compensate.[18]

Type II cells

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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 secretory organelles known as lamellar bodies or lamellar granules, that fuse with the cell membranes and secrete pulmonary surfactant. This surfactant is a film of fatty substances, a group of phospholipids that reduce alveolar surface tension. The phospholipids are stored in the lamellar bodies. Without this coating, the alveoli would collapse. The surfactant is continuously released by exocytosis. Reinflation of the alveoli following exhalation is made easier by the surfactant, which reduces surface tension in the thin fluid 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 the blood–air barrier.[19][20]

Type II cells start to develop at about 26 weeks of gestation, 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 of infant 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 human gene associated with type II pneumocytes, has been identified as a marker in lung 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]

Alveolar macrophages

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The alveolar 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 called pulmonary macrophages, and dust 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]

Clinical significance

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Diseases

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Main articles: Respiratory disease and Alveolar lung disease

Surfactant

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Insufficient surfactant in the alveoli is one of the causes that can contribute to atelectasis (collapse of part or all of the lung). Without pulmonary surfactant, atelectasis is a certainty.[26] The severe condition of acute respiratory distress syndrome (ARDS) is caused by a deficiency or dysfunction of surfactant.[27] Insufficient surfactant in the lungs of preterm infants causes infant respiratory distress syndrome (IRDS). The lecithin–sphingomyelin ratio is a measure of fetal amniotic fluid to indicate lung maturity or immaturity.[28] A low ratio indicates a risk factor for IRDS. Lecithin and sphingomyelin are two of the glycolipids of pulmonary surfactant.

Impaired surfactant regulation can cause an accumulation of surfactant proteins to build up in the alveoli in a condition called pulmonary alveolar proteinosis. This results in impaired gas exchange.[29]

Inflammation

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Pneumonia is an inflammatory condition of the lung tissue, which can be caused by both viruses and bacteria. Cytokines and fluids are released into the alveolar cavity, interstitium, or both, in response to infection, causing the effective surface area of gas exchange to be reduced. In severe cases where cellular respiration cannot be maintained, supplemental oxygen may be required.[30][31]

  • Diffuse alveolar damage can be a cause of acute respiratory distress syndrome(ARDS) a severe inflammatory disease of the lung.[32]: 187 
  • In asthma, the bronchioles 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 an abundance 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.
  • Hypersensitivity pneumonitis

Structural

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Cryptococcosis of lung in patient with AIDS. Mucicarmine stain. Histopathology of lung shows widened alveolar septum containing a few inflammatory cells and numerous yeasts of Cryptococcus neoformans. The inner layer of the yeast capsule stain red.

Almost any type of lung tumor or lung 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 the elastin in the walls of the alveoli is broken down by an imbalance between the production of neutrophil elastase (elevated by cigarette smoke) and alpha-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.
  • Pulmonary alveolar microlithiasis is a rare lung disorder of small stone formation in the alveoli.
  • 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 of fibrosis in the lungs and the onset of idiopathic pulmonary fibrosis.[34]

Fluid

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A pulmonary contusion is a bruise 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.

Coronavirus

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Further information: ACE2 § Coronavirus entry point

Because of the high expression of angiotensin-converting enzyme 2 (ACE2) in type II alveolar cells, the lungs are susceptible to infections by some coronaviruses including the viruses that cause severe acute respiratory syndrome (SARS)[36] and coronavirus disease 2019 (COVID-19).[37]

Additional images

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  • Blood circulation around alveoli
    Blood circulation around alveoli
  • Diagrammatic view of lung showing magnified inner structures including alveolar sacs at 10) and lobules at 9)
    Diagrammatic view of lung showing magnified inner structures including alveolar sacs at 10) and lobules at 9)

See also

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References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pulmonary alveolus

View on Grokipedia
from Grokipedia
The pulmonary alveolus (plural: alveoli) is a tiny, polyhedral air sac forming the terminal units of the 's respiratory tree, where the primary between inhaled oxygen and exhaled occurs across a thin blood-air barrier. These microscopic structures, numbering approximately 480 million in an average adult , cluster into alveolar sacs at the ends of bronchioles and are separated by shared inter-alveolar septa containing a dense network. The alveolar consists mainly of flattened type I pneumocytes, which cover about 95% of the surface area and enable efficient of gases over a barrier as thin as 0.2–1 micrometer. Complementing these are cuboidal type II pneumocytes, which comprise roughly 5% of the surface but about 60% of alveolar epithelial cells and serve as progenitors for epithelial repair. Alveolar macrophages, derived from circulating monocytes, reside on the surface to phagocytose inhaled particles, pathogens, and debris, thereby supporting immune defense. The functional design of the alveoli optimizes through a vast total surface area of approximately 70 square meters in adults, allowing rapid equilibration of oxygen between alveolar air and pulmonary capillaries. , a lipid-protein complex secreted by type II cells (primarily dipalmitoylphosphatidylcholine with proteins SP-A through SP-D), lines the alveolar inner surface to dramatically reduce , preventing collapse () during exhalation and stabilizing alveoli of varying sizes via the law of Laplace. The within alveolar septa, including elastic fibers of and , provides mechanical recoil and structural integrity, enabling the alveoli to inflate during inspiration and deflate passively. Disruptions in alveolar structure or function, such as deficiency or , can impair ventilation-perfusion matching and lead to respiratory insufficiency.

Structure

Location and organization

The pulmonary alveoli represent the terminal expansions of the respiratory tree, forming the primary site of within the lung's respiratory zone. This zone begins at the respiratory bronchioles, where alveoli first appear sparsely along the walls, and extends through alveolar ducts—tubular structures lined almost entirely by alveoli—to alveolar sacs, which are polyhedral clusters of 20 to 30 alveoli sharing a common opening. In adult human lungs, these structures number approximately 480 million, distributed bilaterally across the two lungs. The collective surface area provided by these alveoli totals 70 to 80 square meters in adults, a vast expanse that facilitates efficient by maximizing contact between air and blood. Alveolar septa, the thin walls separating adjacent alveoli, house an extensive network of pulmonary capillaries in close to the epithelial lining, optimizing pathways. Embedded within these septa are elastic fibers, primarily composed of , which confer the lung's , enabling passive expiration and structural integrity during breathing cycles. Alveolar density exhibits regional variations within the human lung, decreasing from the apex to the base in the upright position due to gravitational influences on thoracic stress and expansion. Across , alveolar and surface area scale with metabolic demands; for instance, smaller mammals or those adapted for high oxygen needs, such as bats, possess relatively higher densities to support elevated aerobic capacities compared to larger, less active .

Microanatomy

The pulmonary alveolus features a delicate epithelial lining that forms the primary interface for , consisting of flat squamous type I pneumocytes covering approximately 95% of the surface and cuboidal type II pneumocytes occupying the remaining 5%. This lining, with a total blood-gas barrier thickness ranging from 0.2 to 1.0 μm in regions of direct contact, overlies a fused shared with the underlying , minimizing the path while maintaining structural integrity. Alveolar walls incorporate a network of elastic and fibers that provide essential structural support and elasticity, allowing the alveoli to expand during inspiration and recoil during expiration. Elastic fibers, primarily composed of , enable compliance and prevent , while fibers, including type III variants, offer tensile strength to resist overdistension and maintain wall stability. Interconnecting adjacent alveoli are the pores of Kohn, small fenestrations measuring 10-15 μm in that permit collateral airflow and pressure equalization between neighboring units. These pores, bordered by elastic and reticular fibers, enhance ventilation uniformity without compromising the primary barrier. The interalveolar septa, which separate adjacent alveoli, contain sparse elements including fibroblasts and to preserve a minimal diffusion distance. Fibroblasts contribute to matrix production and remodeling, while support integrity within the septa, ensuring the overall thinness of the structure (typically under 1 μm in gas-exchange zones).

Development

Prenatal development

The prenatal development of the pulmonary alveoli begins with the formation of the lung bud from the ventral wall of the foregut endoderm at approximately day 22 post-fertilization, marking the onset of . This initial outgrowth, known as the respiratory diverticulum, elongates and bifurcates into primary bronchial buds by the end of the fourth week, initiating the embryonic stage (weeks 3-6) where the basic tracheobronchial tree architecture is established. Lung development progresses through five canonical stages: the pseudoglandular stage (weeks 5-17), characterized by extensive branching morphogenesis to form the conducting airways up to the terminal bronchioles; the canalicular stage (weeks 16-25), during which respiratory bronchioles and primitive alveolar ducts emerge with initial vascularization; the saccular stage (weeks 24-38), featuring expansion of terminal air sacs and thinning of the interstitium to prepare for ; and the alveolar stage, which begins around week 36 with the formation of mature alveoli through secondary septation. Branching morphogenesis during these early stages is primarily driven by signaling pathways involving fibroblast growth factor 10 (FGF10), sonic hedgehog (SHH), and bone morphogenetic proteins (BMPs), which regulate epithelial-mesenchymal interactions to generate the intricate airway tree. Vascular development is tightly coupled with epithelial , particularly in the canalicular stage, where capillary networks proliferate and closely appose the epithelial lining to form the foundational blood-air barrier. By approximately week 20, cuboidal epithelial cells differentiate into type I pneumocytes (thin, squamous cells for gas ) and type II pneumocytes (which produce ), with type II cells appearing first in the canalicular phase and giving rise to type I cells during the saccular stage. production by type II pneumocytes begins in the late saccular phase around week 32, stabilizing alveolar structures for postnatal respiration. Genetic factors play a critical role in alveolar formation; for instance, mutations in the FOXF1 gene, a key regulator of mesenchymal development, are associated with alveolar and conditions like alveolar capillary dysplasia, leading to reduced capillary density and impaired septation. Environmental influences, such as maternal smoking, can disrupt branching by altering nicotine exposure effects on fetal epithelial growth and vascular patterning, potentially resulting in fewer airway branches and smaller alveolar units.

Postnatal development

Postnatal development of the pulmonary alveoli involves a phase of rapid proliferation and maturation that continues well after birth, primarily through the process of alveolar septation, where secondary septa form within the saccules to create mature alveoli. At birth, the human lung contains approximately 50 million alveoli, which multiply exponentially during the first two years of life and continue to increase at a slower rate until around age 8, reaching about 480 million in adulthood. This septation and multiplication expand the alveolar surface, tripling in area during the first two years from roughly 3–5 at birth to about 10–15 by age 2, driven by the addition of new alveoli rather than enlargement of existing ones. Environmental factors significantly influence this early growth; adequate supports optimal alveolar multiplication, while can impair it, and postnatal infections or exposure to —particularly in preterm infants—pose risks of disrupted septation and reduced final alveolar number. Hormonal signals, notably glucocorticoids, play a key role in regulating postnatal alveolar maturation by promoting septal formation and epithelial differentiation, though excessive postnatal exposure can alter progenitors and potentially hinder long-term growth. Additionally, epigenetic modifications, such as changes in response to hypoxia, influence in alveolar cells, adapting development to environmental oxygen levels but potentially leading to persistent alterations if hypoxia is prolonged. At birth, type II pneumocytes rapidly adapt production to support the transition to air breathing. With advancing age, the number of alveoli begins to decline after early adulthood, contributing to reduced elasticity and diminished efficiency by age 50 and beyond, as alveolar walls thicken and the overall surface area decreases. This age-related loss, estimated at 10–20% by late adulthood in some studies, exacerbates ventilatory limitations and increases susceptibility to respiratory challenges.

Function

Gas exchange mechanism

The gas exchange mechanism in pulmonary alveoli relies on passive of oxygen (O₂) and carbon dioxide (CO₂) across the thin alveolar-capillary membrane, driven by gradients between alveolar air and pulmonary capillary blood. This process is quantitatively described by Fick's law of diffusion, which posits that the of gas (V) across the membrane is directly proportional to the available surface area (A), the diffusion coefficient of the gas (D), and the difference (ΔP), while inversely proportional to the membrane thickness (T): V=A⋅D⋅ΔPTV = \frac{A \cdot D \cdot \Delta P}{T} /07:_Fundamentals_of_Gas_Exchange/7.02:_Fick's_law_of_diffusion)
The extremely thin barrier provided by type I pneumocytes minimizes T, while the expansive alveolar surface area maximizes A, optimizing diffusion efficiency. Notably, although the molecular size of O₂ is smaller than CO₂, the higher solubility of CO₂ results in a diffusion coefficient approximately 20 times greater, enabling comparable exchange rates despite a smaller ΔP for CO₂. Under normal physiological conditions, alveolar of O₂ (PAO₂) is approximately 100 mmHg, contrasting with 40 mmHg in mixed , which establishes a steep for O₂ uptake. Alveolar PCO₂ remains around 40 mmHg, slightly below the 45-46 mmHg in , facilitating CO₂ elimination. These are optimized by the ventilation-perfusion (V/Q) ratio, typically averaging 0.8 in healthy lungs, which balances alveolar ventilation (V) with (Q) to prevent mismatches that could impair gas transfer. In the bloodstream, O₂ primarily binds to within erythrocytes, vastly increasing transport capacity compared to plasma solubility alone. For CO₂, about 5-10% binds directly to hemoglobin's amino groups, forming , which aids its venous return to the lungs. The enhances overall efficiency by reducing hemoglobin's O₂ affinity in the presence of elevated CO₂ and H⁺ (low ), promoting O₂ unloading in tissues and indirectly supporting CO₂ loading via reciprocal interactions. governs gas solubility in plasma, stating that the concentration of dissolved gas is directly proportional to its , which is essential for the initial dissolution of O₂ and CO₂ prior to hemoglobin binding or formation. Several factors influence efficiency through alterations in Fick's parameters. At high altitudes, reduced barometric lowers inspired PO₂ and thus alveolar PAO₂, diminishing the ΔP for O₂ and inducing hypoxia despite attempts to compensate. Conversely, during exercise, rises proportionally with metabolic demand, increasing pulmonary (Q) and recruiting additional capillaries, which sustains V/Q matching and enhances overall gas transfer when ventilation rises accordingly.

Type I pneumocytes

Type I pneumocytes, also known as alveolar epithelial type I cells, are highly attenuated squamous epithelial cells that cover approximately 95% of the alveolar surface area, providing the primary interface for in the . These cells feature extensive, overlapping cytoplasmic extensions that enable a single cell to span up to 5,000 μm² of surface, while maintaining an extraordinarily thin profile of about 0.2 μm in thickness across their expansive leaflets. This morphology minimizes the distance for oxygen and between the alveolar and pulmonary capillaries, with the containing few organelles—primarily cytoskeletal and —to further reduce barrier thickness and enhance permeability. Type I pneumocytes form tight junctions with adjacent type I cells and type II pneumocytes, creating a continuous, impermeable epithelial barrier that prevents fluid leakage while permitting selective transport. They originate from progenitors in type II pneumocytes through a process of , during which type II cells lose cuboidal features and flatten to adopt the type I . Key markers of this differentiation and mature type I identity include aquaporin-5 (AQP5), a water channel protein expressed on the apical , and T1α (podoplanin), a transmembrane sialoglycoprotein also localized to the apical surface. These markers emerge progressively during , with AQP5 and T1α expression increasing as type II-specific proteins diminish. Due to their delicate structure and limited proliferative capacity, type I pneumocytes exhibit high vulnerability to injury from insults such as , radiation, or infection, often undergoing before other alveolar cells. Repair of the following such damage relies on the of surviving type II pneumocytes into type I cells, restoring the thin barrier essential for gas . AQP5 plays a specialized role in this context by conferring high osmotic water permeability (P_f of 0.06–0.08 cm/s) to type I monolayers, facilitating rapid fluid clearance from the alveolar space to maintain dryness and optimize O₂/CO₂ permeability across the barrier.

Type II pneumocytes

Type II pneumocytes, also known as alveolar epithelial type II cells, are cuboidal epithelial cells that cover approximately 5% of the alveolar surface area but constitute about 60% of the alveolar epithelial cells. These cells are characterized by a rounded morphology with a central nucleus, apical microvilli, and prominent cytoplasmic lamellar bodies, which are specialized organelles responsible for storing and secreting . The lamellar bodies form through the packaging of surfactant components in the Golgi apparatus and are essential for maintaining alveolar stability during respiration. The primary secretory function of type II pneumocytes is the production and release of , a complex that lines the alveolar surface. consists of approximately 90% , predominantly phospholipids such as dipalmitoylphosphatidylcholine (DPPC), and 10% proteins, including surfactant proteins SP-A, SP-B, SP-C, and SP-D. These components work synergistically to reduce at the air-liquid interface in the alveoli, thereby preventing collapse according to , which states that the pressure difference across a spherical surface (ΔP) is given by ΔP = 2γ/r, where γ is and r is the radius; lower γ stabilizes smaller alveoli. is secreted via of lamellar bodies in response to mechanical stretch during , and a portion is recycled through interactions with alveolar macrophages. In addition to their secretory role, type II pneumocytes exhibit regenerative capabilities as progenitor cells within the alveolar epithelium. Following injury, these cells proliferate and differentiate into type I pneumocytes to repair the epithelial barrier, a process tightly regulated by the Wnt/β-catenin signaling pathway, which promotes trans-differentiation by stabilizing β-catenin and activating target genes involved in . This stem-like function ensures alveolar maintenance and restoration after damage from various insults. Postnatal maturation of type II pneumocytes is critical for lung function at birth, with surfactant production initiating around 24 weeks of and ramping up significantly by 32-35 weeks to produce adequate levels that facilitate the transition from fluid-filled to air-filled . This developmental surge in surfactant synthesis underscores the cells' role in neonatal respiratory adaptation.

Alveolar macrophages

Alveolar macrophages are mononuclear that originate from fetal monocytes, which migrate to the developing during embryogenesis and differentiate into mature, long-lived resident cells shortly after birth in a (GM-CSF)-dependent process. These cells adhere to the alveolar epithelial surface, positioning them ideally for constant interaction with the airspaces and inhaled substances. Their core protective behaviors include robust of inhaled pathogens, environmental dust particles, and debris from , which they internalize and degrade within phagolysosomes to maintain alveolar cleanliness and prevent obstruction of sites. Upon encountering threats, alveolar macrophages secrete cytokines such as tumor factor-alpha (TNF-α) to amplify , recruit additional immune cells, and coordinate host defense while also modulating the response to avoid overactivation. In , alveolar macrophages collaborate with type II pneumocytes to clear excess material, processing approximately 10-20% of recycled . Alveolar macrophages exhibit , polarizing into pro-inflammatory M1 or states based on microenvironmental signals like interferon-gamma for M1 activation or interleukin-4 for . The M1 phenotype enhances antimicrobial activity through production and , whereas supports resolution and tissue maintenance via mediators; in humans, many alveolar macrophages co-express markers of both, reflecting a balanced steady-state adaptation to the niche. For effective surveillance, alveolar macrophages express pattern recognition receptors such as (TLR4), which detects from and initiates signaling cascades for release and . To safeguard against prolonged , activated alveolar macrophages undergo programmed , clearing senescent cells via and promoting resolution without tissue damage.

Clinical significance

Surfactant-related disorders encompass a range of conditions stemming from deficiencies or dysfunctions in , a lipid-protein complex essential for reducing alveolar and preventing collapse during respiration. These disorders primarily affect neonates and can lead to severe if untreated, with involving impaired due to alveolar instability. While normal surfactant production by type II pneumocytes maintains , disruptions in its synthesis, regulation, or clearance precipitate these pathologies. Infant respiratory distress syndrome (IRDS), also known as neonatal respiratory distress syndrome, arises predominantly in preterm infants due to insufficient surfactant production, leading to widespread alveolar atelectasis and impaired ventilation. This condition was first linked to surfactant deficiency in 1959 by Avery and Mead, who observed the absence of surface-active material in lung extracts from affected infants. Clinically, IRDS manifests as tachypnea, grunting, and hypoxemia shortly after birth, with an incidence approaching 50-80% in infants born before 28 weeks gestation, though overall rates have declined with preventive measures. Exogenous surfactant replacement therapy, introduced successfully in preterm infants by Fujiwara et al. in 1980, has revolutionized management by restoring alveolar stability and reducing mortality from over 50% to less than 10% in treated cases. Pulmonary alveolar proteinosis (PAP) represents an acquired surfactant-related disorder characterized by autoimmune-mediated accumulation of surfactant-derived lipoproteinaceous material within alveoli, impairing and causing progressive dyspnea. In the autoimmune form, which accounts for approximately 90% of adult cases, neutralizing autoantibodies against (GM-CSF) disrupt function, leading to impaired surfactant clearance. Diagnosis is typically confirmed through (BAL), which yields a characteristic milky, opaque fluid rich in periodic acid-Schiff-positive material, often alongside showing crazy-paving patterns. Standard treatments include whole-lung lavage (WLL), a procedure involving sequential saline instillation to remove accumulated material, and inhaled GM-CSF, both recommended as first-line options by the 2024 European Respiratory Society guidelines; WLL provides symptomatic relief in over 80% of patients. Genetic mutations in surfactant protein genes, particularly SFTPB and SFTPC, underlie hereditary forms of surfactant dysfunction, often presenting as familial IRDS or chronic . Biallelic mutations in SFTPB, encoding protein B (SP-B), cause a lethal recessive disorder with complete absence of functional SP-B, resulting in severe mimicking IRDS in term infants and necessitating for survival. In contrast, heterozygous mutations in SFTPC, encoding protein C (SP-C), lead to a variable including neonatal RDS, childhood-onset , or adult fibrotic patterns, driven by protein misfolding and stress in type II pneumocytes. These genetic disorders collectively account for up to 8% of familial s, with SFTPB mutations occurring in approximately 1 in 1,000,000 live births. Emerging therapies for surfactant-related disorders, particularly SP-B deficiency, focus on gene editing to correct underlying mutations and restore protein expression. Preclinical studies have demonstrated the potential of (AAV)-based / systems, such as AAV6.2FF vectors, to edit SFTPB mutations in alveolar type II cells, achieving targeted correction without off-target effects in animal models. These approaches aim to provide a curative alternative to transplantation, especially given the high incidence of IRDS in preterm infants (up to 1 in 1,000 deliveries under 35 weeks), where genetic screening could identify at-risk cases early. Clinical translation remains preclinical as of 2025, with emphasis on advancing to trials for and long-term .

Inflammatory and infectious conditions

Inflammatory and infectious conditions of the pulmonary alveoli encompass a range of acute and chronic processes that disrupt alveolar integrity through invasion or dysregulated immune responses, leading to impaired and potential long-term damage. , a primary example, results from bacterial or viral infection of the lung parenchyma, causing inflammation that fills alveolar spaces with exudate. , often triggered by , prompts a robust influx into the alveoli, leading to consolidation where airspaces are occupied by , , and cellular debris, which hinders oxygen . , by contrast, typically involves mononuclear cell infiltration and less organized alveolar filling, though it can predispose to secondary bacterial superinfection with similar neutrophil-mediated effects. Acute respiratory distress syndrome (ARDS) represents a severe inflammatory response often initiated by or trauma, culminating in characterized by endothelial and epithelial injury, protein-rich , and hyaline membrane formation. This —driven by elevated levels of pro-inflammatory mediators like TNF-α and IL-6—amplifies recruitment and in the alveoli, exacerbating capillary leakage and ventilation-perfusion mismatch. Diagnosis relies on the criteria, which define ARDS by acute onset within one week of a known , bilateral opacities on not fully explained by cardiac , and hypoxemia with a PaO₂/FiO₂ of ≤300 mmHg on ≥5 cmH₂O. Severe acute respiratory syndrome coronavirus 2 () infection, as seen in , targets alveolar type II pneumocytes via binding to (ACE2) receptors, inducing direct cytopathic effects and a dysregulated that forms hyaline membranes and akin to ARDS. This alveolar injury contributes to acute and, in prolonged cases, increases the risk of in , with post-2023 studies reporting persistent interstitial changes in up to 17.5% of survivors, linked to initial severity and prolonged hospitalization. Chronic bronchitis, while primarily affecting larger airways, overlaps with alveolar inflammation in the context of (COPD), where persistent exposure to irritants recruits alveolar macrophages and neutrophils, promoting low-grade parenchymal and hypersecretion that indirectly impairs alveolar function. Treatment often involves inhaled corticosteroids to suppress this , reducing frequency. Incidence of chronic bronchitis has risen with increasing , with studies showing a 12-33% higher odds of COPD exacerbations per increase in particulate matter or indoor pollutants.

Structural and fibrotic disorders

Structural and fibrotic disorders of the pulmonary alveoli involve pathological remodeling that disrupts the delicate architecture essential for , leading to irreversible loss of alveolar integrity and function. These conditions often arise from chronic insults such as or genetic predispositions, resulting in either destructive enlargement of airspaces or excessive deposition of . exemplifies alveolar wall destruction, while (IPF) represents progressive fibrotic scarring, both severely impairing the alveolar surface area available for diffusion. Emphysema is characterized by the permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by destruction of alveolar walls without significant . In smokers, this pathology stems from an imbalance in the protease-antiprotease system, where cigarette smoke recruits neutrophils that release , a proteolytic that degrades in the alveolar . This enzymatic degradation is exacerbated by from smoke, which inactivates antiproteases like (AAT), leading to unchecked tissue breakdown. The centrilobular form, predominant in (COPD), primarily affects the upper lobes and can reduce the alveolar surface area by 20-50%, diminishing efficiency and contributing to . Idiopathic pulmonary fibrosis (IPF) manifests as a progressive interstitial pneumonia with scarring that thickens and stiffens alveolar walls, ultimately replacing functional parenchyma with fibrotic tissue. Histologically, IPF features usual interstitial pneumonia (UIP), marked by temporal heterogeneity with fibroblast foci—clusters of actively proliferating myofibroblasts driving extracellular matrix deposition. High-resolution computed tomography (HRCT) typically reveals a UIP pattern, including subpleural basal reticular abnormalities, honeycombing, and traction bronchiectasis, aiding diagnosis without biopsy in many cases. The median survival post-diagnosis is 3-5 years, with respiratory failure as the primary cause of death due to escalating fibrosis that obliterates alveolar units. Alpha-1 antitrypsin deficiency (AATD) is a that predisposes individuals to early-onset through inherited protease-antiprotease imbalance. Mutations in the SERPINA1 gene reduce functional AAT levels, allowing unchecked activity to degrade alveolar , particularly in the lower lobes, often manifesting in nonsmokers by age 30-40. Augmentation therapy, involving weekly intravenous infusions of purified AAT, was first approved in 1987 and has been shown to elevate serum and epithelial lining fluid AAT levels above the protective threshold, slowing progression in deficient patients. Recent advancements post-2023 have reinforced the role of antifibrotic therapies in managing fibrotic alveolar disorders like IPF. , a targeting fibrogenic pathways, has demonstrated sustained slowing of forced decline in long-term extension trials, with benefits persisting beyond initial approval studies when continued for up to five years. These updates highlight nintedanib's efficacy in reducing acute exacerbations and stabilizing lung function, offering improved despite the inexorable nature of alveolar .

Fluid accumulation disorders

Fluid accumulation disorders in the pulmonary alveoli primarily manifest as , a condition characterized by the abnormal buildup of fluid in the alveolar spaces and , which severely impairs and can lead to . This occurs through an imbalance in Starling forces across the alveolar-capillary membrane, where elevated hydrostatic pressure in pulmonary capillaries exceeds , driving fluid leakage as a into the alveoli. Cardiogenic , often resulting from left ventricular failure, exemplifies this hydrostatic mechanism, while non-cardiogenic forms involve increased . In cardiogenic pulmonary edema, the transudative fluid accumulation disrupts the thin alveolar barrier, reducing diffusion capacity and causing . Treatment focuses on addressing the underlying pressure imbalance, with such as promoting to reduce preload and alleviate symptoms like dyspnea. Noninvasive positive pressure ventilation, including (CPAP), supports alveolar recruitment and decreases , often averting the need for . High-altitude pulmonary edema (HAPE) represents a non-cardiogenic variant triggered by rapid ascent to elevations above 2500 meters, affecting unacclimatized individuals through hypoxia-induced pulmonary . This leads to uneven and regional overperfusion of alveolar capillaries, elevating local hydrostatic pressures and causing patchy fluid exudation into alveoli. Incidence among climbers and trekkers ascending over 600 meters per day in regions like the or is approximately 4%, though it rises to 15% in rapid ascents to extreme heights such as 5500 meters. Neurogenic pulmonary edema arises acutely following severe central nervous system trauma, such as traumatic brain injury, due to a massive catecholamine surge that disrupts the blood-brain barrier (BBB) and increases pulmonary endothelial permeability. This sympathetic overactivation elevates systemic vascular resistance and pulmonary capillary pressure, forcing fluid into the alveolar interstitium and spaces via altered Starling dynamics. Management emphasizes supportive measures, including osmotherapy with agents like mannitol or hypertonic saline to mitigate BBB-related cerebral edema and indirectly stabilize pulmonary involvement, alongside mechanical ventilation for oxygenation. Diagnosis of these disorders relies on imaging and biomarkers to differentiate cardiogenic from non-cardiogenic etiologies. Chest X-ray findings, such as Kerley B lines indicating interstitial edema, along with of pulmonary vessels and perihilar opacities, support the presence of alveolar fluid overload. Elevated B-type natriuretic peptide (BNP) levels exceeding 100 pg/mL strongly suggest a cardiogenic origin by reflecting ventricular strain, aiding in prompt therapeutic stratification.

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