Research Area

Respiratory System Development


Respiratory system development overview

The respiratory system includes organs such as the nose, pharynx, larynx, trachea, bronchi, and lungs, which are divided into upper and lower respiratory tracts. The part above the throat is called the upper respiratory tract and consists of the nose, pharynx, and larynx. The part below the larynx is called the lower respiratory tract, including the trachea, bronchus, and lungs. The respiratory system mainly has functions such as respiratory, defense, metabolism, nerve and endocrine. The respiratory system matures by the age of 20, and the structure of the respiratory system gradually ages with age. Before the age of 20, the lungs grew and matured, and the number of alveoli reached the highest peak at 10-12 years old. At about 20 to 25 years of age, the respiratory system is optimally functional, and then begins to decline with age; unless suffering from disease, the respiratory system maintains adequate gas exchange throughout its lifetime. Affected by environmental, immune, nutritional, smoking, sleep and other factors and other systems (such as endocrine, nervous, digestive tract and cardiovascular), the elderly are often accompanied by chronic damage to the respiratory system. Although it is difficult to estimate the effect of age on the respiratory system, as the age increases, the structure, and function of the respiratory system will gradually change. It is easy to be damaged, the elderly is prone to respiratory failure in the occurrence of bronchial asthma, chronic obstructive pulmonary disease, lung infection and other diseases, and the mortality rate is significantly increased in younger patients. At the beginning of the fourth week, a longitudinal shallow groove appeared in the middle of the bottom wall of the original pharyngeal end, called the tracheal groove. The stenosis of the stenosis was gradually deepened, forming a blind sac on the ventral side of the esophagus, called the laryngotracheal diverticulum, which is the laryngotracheal tube. The interstitial space between the laryngotracheal diverticulum and the esophagus is called the tracheal esophageal septum. At the end of the fourth week, the end of the laryngotracheal diverticulum was swollen into two left and right, called lung buds, which are the primordium of the bronchi and lungs. The lung buds are repeatedly branched to form the bronchial tree in the lungs. In the seventh month, the number of alveoli increased, and alveolar epithelium showed type 2 cells in addition to type 1 cells and secreted surface-active substances. The capillaries in the alveolar septum were also abundant, so 7 months of premature infants could survive and be born. In the first few weeks, the lungs experienced a rapid survival phase, when the alveoli increased, the alveolar wall became thinner, the fluid in the alveolar cavity was gradually absorbed, the type 2 cells increased, and the amount of surfactant released increased. From birth to early childhood, the lungs continue to develop, and the number of alveoli continues to increase.

Respiratory system development research status


Nose: The nose is the portal of the respiratory system and consists of the outer nose, nasal cavity and sinuses. The inner surface of the nasal cavity is a mucous membrane composed of an epithelium and a lamina propria. The deep part of the mucosa is connected to the perichondrium, periosteum or skeletal muscle. According to the structure and function, the nasal mucosa can be divided into the vestibular, respiratory and olfactory parts. In the elderly, the nasal cartilage elasticity is reduced, the tip of the nose is slightly drooping, the nasal cavity is deformed and widened; the turbinate is atrophy, the inferior turbinate blood vessels are cavernous-like degeneration, and the middle and lower turbinate are narrowed; the nasal mucosa is atrophied and thin, pale or slightly reddish. The cilia transmission rate is slowed down; the glandular atrophy in the lamina propria of the nasal mucosa is atrophy; the maxillary sinus mucosal epithelial cells, the mucous gland and the blood vessel wall have fat deposits; the direction of the anterior nasal opening is changed from the forward horizontal opening to the lower side. Throat: The throat is an important organ for breathing and vocalization. The laryngeal cartilage of the elderly is calcified or ossified due to aging, males occur earlier than women, and almost completely ossified at the age of 80; thyroid cartilage ossification; collagen fibers degeneration of the sacral cartilage; The elastic tissue undergoes atrophic changes; the vocal cords are atrophied, the vocal cords are reduced in elastic fibers and muscle fibers, the collagen fibers are proliferated, and the structure is disordered; the laryngeal mucosa is thinned, the epithelium often has parakeratosis or hyperkeratosis, lamina propria, and fat loss. Thoracic: The thorax is made up of vertebrae, ribs, sternum and scapula. With age, the vertebrae and sternum appear degenerative changes, the spine appears posterior to the lord, the intervertebral space becomes narrow, the thoracic vertebrae bend back and the sternum protrudes; The ribs are slanted from the upper rear to the lower and the lower direction from the back to the front, the upper rib gap is widened, the rib cartilage is calcified, the rib cage joint is calcified, the joint ligament is hardened, and the elasticity is lowered; The defect leads to the loss of the continuity of the diaphragm and also increases with the age. The anterior and posterior diameter of the thorax of the elderly is increased, the left and right diameter is reduced, the upper part of the thorax is widened, the lower part is narrowed, and the flattened shape becomes a barrel shape. For the barrel chest, this is a characteristic manifestation of chest aging. With the aging of the pleural fibrous tissue hyperplasia, pleural thickening, pleural wall layer and visceral layer can be partially adhered, and even thin, dry, reduced transparency and calcification. Trachea, bronchus and small airway: The trachea is a tubular structure with the upper end starting from the annular cartilage, extending downward through the neck into the chest, and the lower end of the trachea is divided into left and right bronchus. With age, degenerative changes occur in the trachea, bronchi, and small airways. The tracheal lumen of the elderly is dilated, the internal diameter is increased, and the female is more obvious than the male; the elastic tissue of the wall is reduced, the collagen fibers are increased, accompanied by hyaline degeneration, the bronchial lumen is narrowed, the small airway lumen is narrowed, or accompanied by early small airway collapse or closure, small airway mucosa atrophy and wall elastic loss are more obvious; tracheal and bronchial mucosa epithelial atrophy or local hyperplasia, such as mucosal damage, prone to squamous metaplasia. Mucosal cells are reduced, cilia gradually fall off, lodging and adhesion. Small airway goblet cells increase. Submucosal smooth muscle atrophy, lymphocytic infiltration. Degenerative changes in the mucosal glands of the trachea and bronchi. Lung: The lung is a spongy organ with elasticity, like a cone. The upper end is the tip of the lung, the lower end is the lung base, the inner side is called the mediastinum, and the outer side is called the rib surface. The surface of the lungs is covered with a pleural visceral layer, and a polygonal shape can be observed through the visceral layer of the pleura.

Respiratory system development clinical applications

The β2 adrenergic receptor is one of the main targets for the treatment of asthma and chronic obstructive pulmonary disease. 22 adrenergic receptor agonists are an effective drug for relieving and controlling asthma symptoms. It can relax airway smooth muscle, increase mucociliary clearance, reduce vascular exudation, regulate mediator release of mast cells and eosinophils, and prevent allergic asthma. According to the pipeline database, there are currently 45 β2 adrenergic receptor agonists on the market, and the number of new drugs developed for this target is also the highest, with inhaled long-acting β2 receptor agonists (LABA). Inflammation is one of the factors that cause the onset of respiratory diseases and is difficult to control. Glucocorticoid receptors are effective drug targets for controlling airway inflammation. Inhaled glucocorticoids can fundamentally treat asthma, reduce seizures, and improve lung function in patients. It has become a first-line treatment for asthma. The newly inhaled glucocorticoids (ICS) that are now on the market include mometasone furoate, fluticasone furoate, and ciclesonide. The research of new glucocorticoid drugs is strong, and the number of drugs in preclinical and clinical research and development is high. Histamine is an attractive substance found early. At least three subtypes of histamine receptors are widely present in various tissues of the human body. The histamine H1 receptor is closely related to type I allergic reaction (allergic reaction). H1 receptor blockers have a certain inhibitory effect on allergic reactions and can be used for moderate allergic asthma and allergic asthma with rhinitis. The marketed drugs include ketotifen, Avastin, and astemizole. In recent years, phosphodiesterase 4 (PDE4) has been identified as a new therapeutic target for respiratory diseases. PDE4 selective inhibitors can increase intracellular cAMP levels, down-regulate the release of inflammatory mediators, and produce inflammatory cytokines. Two new PDE4 inhibitors, cilomilast and roflumilast, have been developed. However, some of the results of the Phase III trial of cilastatin have some problems in terms of drug efficacy and safety, which led to the further development of the drug. At present, the number of drugs under investigation for such targets is small, and only two are in preclinical varieties. Leukotriene modulators are a new class of drugs that have been found to treat bronchial asthma in recent years. A cysteinyl leukotriene receptor antagonist whose target is a cysteine leukotriene receptor and such representative drugs are zafirlukast, pranlukast, and montelukast. The number of drugs under investigation for such targets is currently small. It is worthy of attention that the drug is targeted at the muscarinic choline receptor (M receptor). Although the total number of varieties in the study is less than other targets, the listed drugs account for a large proportion, and there are varieties in each stage of development. Recent studies on specific M receptor antagonists have made great progress, and most studies have focused on finding selective M3 receptor antagonists because M3 receptor antagonists have good therapeutic potential for the pathophysiological state of smooth muscle. Due to the particularity of the organs and tissues of the respiratory medicine and the particularity of its administration route, its development and research have its own characteristics. According to the chemical characteristics of the drug, to achieve high efficacy and low toxicity, in addition to the traditional oral and injectable dosage forms, the route of administration of the respiratory system is often carried out by local administration, which requires some special dosage forms. In recent years, various new respiratory drug preparations have been developed, such as oral rapid disintegrating tablets, sustained release preparations, controlled release preparations, oral inhalers, nasal inhalants, and transdermal patches. The new product involves a single preparation of paeoniflorin and a combination preparation of antitussive, antiasthmatic (northostatic blood) and antihistamines. Japan's Yamauchi Co., Ltd. and East Asia Pharmaceutical Co., Ltd. have jointly launched the oral drug amphoteric hydrochloride oral rapid disintegration tablets, which can be disintegrated in the oral cavity. The prednisolone sodium orally disintegrating tablet developed by BioMarin was approved by the FDA in 2006 and is an adrenal corticosteroid for indications such as asthma. ICS/LABA compound preparations have become the number one hot spot in clinical research, and currently five varieties have been listed worldwide. In recent years, the launch of new products such as one-time/d administration and combination therapy will promote the application of asthma drugs, improve patient compliance and reduce adverse reactions.

Reference

  1. Rubarth L B, Quinn J. Respiratory Development and Respiratory Distress Syndrome. Neonatal Network. 2015, 34(4):
  2. Adcock N. Bioanalysis for the development of respiratory drugs: what are the challenges? Bioanalysis. 2014, 6(9):1143-1145.
  3. Polgar G, Weng T R. The functional development of the respiratory system from the period of gestation to adulthood. American Review of Respiratory Disease. 1979, 120(3):625.
  4. Lock M C, Mcgillick E V, Orgeig S, et al. Mature Surfactant Protein-B Expression by Immunohistochemistry as a Marker for Surfactant System Development in the Fetal Sheep Lung. Journal of Histochemistry & Cytochemistry Official Journal of the Histochemistry Society. 2015, 63(11):866-78.
  5. Hitchcock K R. Lung development and the pulmonary surfactant system: hormonal ifluences. Anatomical Record Advances in Integrative Anatomy & Evolutionary Biology. 2010, 198(1):13-34.

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