A team from the University of Washington School of Medicine (St. Louis, Missouri) was the first to describe the molecular mechanism of tracheobronchial mucus hypersecretion in severe respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis. Based on the results obtained, the authors of the work have developed a series of drugs that block this process. The work was published on November 26 in the journal Journal of Clinical Investigation.
As it was established earlier, at the beginning of the signal chain leading to overexpression of the MUC5AC gene, which is responsible for the secretion of mucus by epithelial cells of the respiratory tract, there is an overproduction of immune cells in response to the ingestion of an allergen or virus, the protein interleukin 13 (IL-13), into the respiratory tract. However, it has not yet been understood exactly how IL-13 induces MUC5AC overexpression.
A team led by Professor Michael J. Holtzman found that the CLCA1 gene, which is activated by IL-13, plays a key role in this mechanism. This gene is responsible for the production of the signaling molecule of the same name, which, in turn, penetrates cell membranes and activates the MAPK13 gene. Isolation of the enzyme of the same name, which directly stimulates the expression of MUC5AC.
All the work to establish the links of the chain was carried out on isolated human epithelial cells, since in commonly used laboratory animals, the mechanism for the production of tracheobronchial mucus turned out to be different from that in humans. The obtained results were confirmed by the study of samples of lung tissue from patients with severe COPD. In them, in addition to an excess of mucus, an increased level of CLCA1 molecules and the MAPK13 enzyme was found.
The authors concluded that the main target of a potential drug designed to stop sputum hypersecretion should be the MAPK13 gene, whose expression product regulates its secretion. MAPK13 inhibitors were developed by the authors on the basis of BIRB-796, an already known blocker of the MAPK14 gene, to which MAPK13 is 60 percent homologous. Molecular adjustments have been made to improve the potency of this substance against MAPK13.
Testing of a series of new drugs-inhibitors of MAPK13 in vitro showed that they almost a hundred times reduce the production of mucus by epithelial cells. As the authors note, such a high efficiency of these substances also indirectly proves the correctness of the definition of the underlying mechanism of the secretion process.
In addition to COPD, asthma and cystic fibrosis, diseases in which hypersecretion of mucus blocking the airways is the main risk factor, the developed drugs can also be used for viral respiratory infections and allergies, Holtzman believes. "Our research shows that a similar mechanism works in these cases. Because MAPK13 inhibitors are active in both the upper and lower airways, they are suitable for the treatment of a wide range of respiratory diseases," he said.
Chronic respiratory tract disease with copious sputum, especially COPD, is the third leading cause of premature death in the United States and other countries around the world. Currently, there are no effective drugs aimed at reducing the secretion of tracheobronchial mucus in medical practice.
In 1963, Laurell and Eriksson observed that individuals with α1-antitrypsin deficiency, which inhibit a number of serum proteinases such as neutrophil elastase, have an increased risk of developing emphysema, since neutrophil elastase destroys elastin, which is a major component of the alveolar wall. In addition, elastin fragments act on macrophages and neutrophils to support inflammation. Although today α1-antitrypsin deficiency is differentiated from the concept of COPD, an imbalance of the enzyme system occurs in COPD in the present sense of this term. It is known that macrophages, neutrophils and epithelial cells secrete a combination of proteases. The activity of the antiprotease system is reduced due to oxidative stress, exposure to tobacco smoke and other factors. Probably neutrophil elastase is not important in COPD, in the pathogenesis of which the proteases are played by neutrophilic cathepsin G, neutrophilic proteinase-3, macrophage cathepsins (especially cathepsins B, L and S), and various matrix metalloproteinases.
Oxidative stress
The role of oxidative stress is evidenced by markers found in the liquid on the surface of the epithelium, exhaled air and urine of smokers and patients with COPD - hydrogen peroxide (H2O2) and nitric oxide (NO), formed during smoking or released from leukocytes and epithelial cells during inflammation. H 2 O 2 appears in an increased amount in the exhaled air in patients both in remission and during an exacerbation, and the NO content increases in the exhaled air during an exacerbation. The concentration of isomeraprostaglandin isoprostane F2α-III, a biomarker of oxidative stress in the lungs in vivo, formed during free radical oxidation of arachidonic acid, increases in exhaled air condensate and urine in patients with COPD in comparison with healthy people and increases even more during exacerbation.
Oxidants destroy biological molecules: proteins, fats, nucleic acids, which leads to dysfunction and death of cells, destruction of the extracellular matrix. Also, due to oxidative stress, the proteinase-antiproteinase imbalance is aggravated by inactivation of antiproteinases and by activation of proteinases such as metalloproteinases. Oxidants increase inflammation by activating NF-kB, which promotes the expression of inflammatory genes such as IL-8 and TNF-α. Finally, oxidative stress can cause reversible bronchial obstruction: H 2 O 2 leads to the contraction of smooth muscle cells in vitro, and isoprostane F2α-III in humans is an agent causing severe bronchial obstruction.
The course of the pathological process
Pathophysiological changes in COPD include the following pathological changes:
hypersecretion of mucus,
dysfunction of the cilia,
bronchial obstruction
destruction of the parenchyma and emphysema of the lungs,
disorders of gas exchange,
pulmonary hypertension
pulmonary heart,
systemic manifestations.
Hypersecretion of mucus
Hypersecretion of mucus is caused by stimulation of the secreting glands and goblet cells by leukotrienes, proteinases, and neuropeptides.
Cilia dysfunction
The ciliated epithelium undergoes squamous metaplasia, which leads to impaired mucociliary clearance (impaired evacuation of sputum from the lungs). These initial manifestations of COPD can persist for many years without progressing.
Pathophysiological changes in COPD include the following pathological changes:- hypersecretion of mucus,
- dysfunction of the cilia,
- bronchial obstruction
- destruction of the parenchyma and emphysema of the lungs,
- disorders of gas exchange,
- pulmonary hypertension
- pulmonary heart,
- systemic manifestations.
Hypersecretion of mucus
Hypersecretion of mucus is caused by stimulation of the secreting glands and goblet cells by leukotrienes, proteinases, and neuropeptides.Cilia dysfunction
The ciliated epithelium undergoes squamous metaplasia, which leads to impaired mucociliary clearance (impaired evacuation of sputum from the lungs). These initial manifestations of COPD can persist for many years without progressing.Bronchial obstruction
The following causes of bronchial obstruction are distinguished:- Irreversible:
- Airway remodeling and fibrosis,
- Loss of elastic traction of the lung as a result of destruction of the alveoli,
- Destruction of the alveolar support of the lumen of the small airways;
- Reversible:
- Accumulation of inflammatory cells, mucus and plasma exudate in the bronchi,
- Contraction of the smooth muscles of the bronchi,
- Dynamic hyperinflation during exercise.
Pulmonary hyperinflation
Pulmonary hyperinflation (PHI) is an increase in the airiness of the lung tissue, the formation and increase of an "air cushion" in the lungs. Depending on the cause of the occurrence, it is divided into two types:Static PHI: due to incomplete emptying of the alveoli on exhalation due to a decrease in elastic traction of the lungs
Dynamic PHI: due to a decrease in expiratory time under conditions of pronounced restriction of expiratory airflow From the point of view of pathophysiology, PHI is an adaptive mechanism, as it leads to a decrease in airway resistance, an improvement in air distribution and an increase in minute ventilation at rest. However, LGI leads to the following adverse consequences:
Weakness of the respiratory muscles. The diaphragm is shortened and flattened, which makes its contraction ineffective.
Restriction of the increase in tidal volume during exercise. In healthy people, during exercise, an increase in the minute volume of respiration occurs due to an increase in the frequency and depth of respiration. In patients with COPD, pulmonary hyperinflation increases during exercise, since an increase in NPV in COPD leads to a shortening of expiration, and even more air is retained in the alveoli. An increase in the "air cushion" does not significantly increase the depth of breathing.
Hypercapnia during exercise. Due to a decrease in the ratio of OOL to VC due to a decrease in VC due to PHI, an increase in PaCO2 in arterial blood occurs.
Increasing the elastic load on the lungs.
Pulmonary hypertension. Ultimately, PHI leads to pulmonary hypertension.
Emphysema of the lungs
The destruction of the parenchyma leads to a decrease in the elastic traction of the lungs, and therefore is directly related to the limitation of the air flow rate and an increase in air resistance in the lungs. Small bronchi, losing contact with the alveoli, which were previously in a straightened state, collapse and cease to be passable.Gas exchange disorders
Airway obstruction, parenchymal destruction and pulmonary blood flow disorders reduce the lung capacity for gas exchange, which leads first to hypoxemia and then to hypercapnia. The correlation between the values of lung function and the level of arterial blood gases is poorly determined, but with FEV1 more than 1 liter, significant changes in the blood gas composition rarely occur. In the initial stages, hypoxemia occurs only with physical exertion, and as the disease progresses, even at rest.Pulmonary hypertension
Pulmonary hypertension develops at stage IV - an extremely severe course of COPD, with hypoxemia (PaO2 less than 8 kPa or 60 mm Hg) and often also hypercapnia. This major cardiovascular complication of COPD is associated with a poor prognosis. Usually, in patients with severe COPD, the pressure in the pulmonary artery at rest is moderately elevated, although it can increase with exertion. The complication progresses slowly, even without treatment. The development of pulmonary hypertension is related to vasoconstriction of the lungs and thickening of the vascular wall due to remodeling of the pulmonary arteries, destruction of pulmonary capillaries in emphysema, which further increases the pressure required for blood to pass through the lungs. Vasoconstriction can occur due to hypoxia, which causes contraction of the smooth muscles of the pulmonary arteries, disruption of the mechanisms of endothelium-dependent vasodilation (decrease in NO production), pathological secretion of vasoconstrictor peptides. Vascular remodeling is one of the main reasons for the development of pulmonary hypertension, in turn, due to the release of growth factors or due to mechanical stress during hypoxic vasoconstriction.Pulmonary heart
Pulmonary hypertension is defined as "right ventricular hypertrophy resulting from diseases affecting the function and / or structure of the lungs, excluding those lung disorders that result from diseases primarily affecting the left heart, as in congenital heart diseases." Pulmonary hypertension and reduction of the vascular bed due to emphysema lead to hypertrophy of the right ventricle and its failure only in some patients.Systemic manifestations
In COPD, there is systemic inflammation and skeletal muscle dysfunction. Systemic inflammation is manifested by the presence of systemic oxidative stress, increased concentration of circulating cytokines, and activation of inflammatory cells. Skeletal muscle dysfunction is manifested by loss of muscle mass and various bioenergetic disorders. These manifestations lead to a limitation of the patient's physical capabilities, reduce the level of health, and a deterioration in the prognosis of the disease.A team from the University of Washington School of Medicine (St. Louis, Missouri) first described the molecular mechanism of tracheobronchial mucus hypersecretion in severe respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis. Based on the results obtained, the authors of the work have developed a series of drugs that block this process. The work was published on November 26 in the journal Journal of Clinical Investigation.
As it was established earlier, at the beginning of the signal chain leading to overexpression of the MUC5AC gene, which is responsible for the secretion of mucus by epithelial cells of the respiratory tract, there is an overproduction of immune cells in response to the ingestion of an allergen or virus, the protein interleukin 13 (IL-13), into the respiratory tract. However, it has not yet been understood exactly how IL-13 induces MUC5AC overexpression.
A team led by Professor Michael J. Holtzman found that the CLCA1 gene, which is activated by IL-13, plays a key role in this mechanism. This gene is responsible for the production of a signaling molecule of the same name, which, in turn, penetrates cell membranes and activates the MAPK13 gene. Isolation of the enzyme of the same name, which directly stimulates the expression of MUC5AC.
All the work to establish the links of the chain was carried out on isolated human epithelial cells, since in commonly used laboratory animals, the mechanism for the production of tracheobronchial mucus turned out to be different from that in humans. The obtained results were confirmed by the study of lung tissue samples from patients with severe COPD. In them, in addition to an excess of mucus, an increased level of CLCA1 molecules and the MAPK13 enzyme was found.
The authors concluded that the main target of a potential drug designed to stop sputum hypersecretion should be the MAPK13 gene, whose expression product regulates its secretion. MAPK13 inhibitors were developed by the authors on the basis of BIRB-796, an already known blocker of the MAPK14 gene, to which MAPK13 is 60 percent homologous. Molecular adjustments have been made to improve the potency of this substance against MAPK13.
In vitro testing of a series of new drugs-inhibitors of MAPK13 showed that they almost a hundredfold reduce the production of mucus by epithelial cells. As the authors note, such a high efficiency of these substances also indirectly proves the correctness of the definition of the underlying mechanism of the secretion process.
In addition to COPD, asthma and cystic fibrosis, diseases in which hypersecretion of mucus blocking the airways is the main risk factor, the developed drugs can also be used for viral respiratory infections and allergies, Holtzman believes. "Our research shows that a similar mechanism works in these cases. Because MAPK13 inhibitors are active in both the upper and lower airways, they are suitable for the treatment of a wide range of respiratory diseases," he said.
Chronic respiratory tract disease with copious sputum, especially COPD, is the third leading cause of premature death in the United States and other countries around the world. Currently, there are no effective drugs aimed at reducing the secretion of tracheobronchial mucus in medical practice.
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