Materiały źródłowe

• #1 Pathophysiology Of Asthma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551579/

  Asthma is most likely transmitted by multiple genes, with some variation of locus heterogeneity and polygenic inheritance leading to asthma expression being multifaceted. […] Atopy or IgE antibodies attack specific antigens or pollutants, which can contribute to the disease. Research has shown that asthma was closely related to the total IgE serum level. […] The early phase is initiated by IgE antibodies that are sensitized and released by plasma cells. These antibodies respond to certain triggers in the environment, such as the risk factors listed above. IgE antibodies then bind to high-affinity mast cells and basophils. When a pollutant or risk factor gets inhaled, the mast cells release cytokines and eventually de-granulate. Released from mast cells are histamine, prostaglandins, and leukotrienes. These cells, in turn, contract the smooth muscle and cause airway tightening.

• #1 Asthma: Types, Causes, Symptoms, Diagnosis & Treatment

  https://my.clevelandclinic.org/health/diseases/6424-asthma

  The normal airways of a woman having an asthma attack become constricted, inflamed and full of mucus. […] Asthma causes bronchospasms, inflammation, thick mucus and constriction in the airways. […] During an asthma attack, three things can happen: Bronchospasm: The muscles around the airways constrict (tighten). When they tighten, it makes your airways narrow. Air cannot flow freely through constricted airways. […] Inflammation: The lining of your airways becomes swollen. Swollen airways dont let as much air in or out of your lungs. […] Mucus production: During the attack, your body creates more mucus. This thick mucus clogs airways. […] You might also hear an asthma attack called an exacerbation or a flare-up. Its the term for when your asthma isnt controlled. […] Asthma has multiple causes: Allergic: Some peoples allergies can cause an asthma attack. Allergens include things like molds, pollens and pet dander.

• #1 Asthma: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/296301-overview

  Asthma is a common chronic disease worldwide and affects approximately 25 million persons in the United States. The pathophysiology of asthma is complex and involves airway inflammation, intermittent airflow obstruction, and bronchial hyperresponsiveness. […] The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence of airway edema and mucus secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway remodeling are present. […] The presence of airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to numerous exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth muscle and indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast cells or nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates with the clinical severity of asthma.

• #1 Bronchial Asthma: Etiology, Pathophysiology, Diagnosis and Management

  https://austinpublishinggroup.com/pulmonary-respiratory-medicine/fulltext/ajprm-v9-id1085.php

  The airways of asthmatic individuals are characterized by a T-Helper cell (Th)-2-profile inflammation consisting of an overabundance of eosinophils, mast cells and Th2 lymphocytes. These inflammatory cells release mediators that trigger bronchoconstriction, mucous secretion and, possibly, remodeling. […] The inflammatory mediators that drive this process include the Th2 cytokines Interleukin (IL)- 4, IL-5, IL-9 and IL-13, Transforming Growth Factor (TGF)-beta, Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF), lipid mediators and histamine. Some of these mediators, such as TGFbeta, IL-11 and IL-17, have potent remodelling properties. […] The mechanisms of nocturnal bronchial asthma are complex and involve the daytime antigen-provoked release of pro-inflammatory mediators from mast and eosinophil cells over the span of several hours thereafter, which results by the end of the day in the exacerbation of inflammation, smooth muscle bronchospasm and contraction, and over-stimulation of mucus glands with mucus hypersecretion of the small airways of the lung.

• #1 The Inflammatory Response in the Pathogenesis of Asthma

  https://www.degruyterbrill.com/document/doi/10.7556/jaoa.2011.20014/html?lang=en&srsltid=AfmBOopxpev5zIpMQFpuD0rlrxJaZlFnnUOkuEw61BOH7g2ng0jV_u2s

  The respiratory epithelium is an integral part of innate immunity and the inflammatory response, and it is capable of producing numerous mediators that can prime and activate many arms of the immune system. […] The airway epithelium produces large amounts of inflammatory cytokines, including TNF-, IL-1, and IL-6. […] These proteins have widespread effects on a wide variety of cells, including leukocytes, in the immune system. […] The effects serve to upregulate inflammatory genes, increase the release of cytokines and chemokines, and expand inflammatory cell numbers. […] The central component of allergic asthma is the development of an immunoglobulin E (IgE) antibody-mediated response to allergens that requires the interaction of a number of leukocytes. […] Binding of allergen to IgE on the cell surface induces a signal transduction cascade that results in the release of mediators.

• #1 Current Understanding of Asthma Pathogenesis and Biomarkers

  https://www.mdpi.com/2073-4409/11/17/2764

  Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most important pathological process for asthma, which is mediated by Th2 cytokines, such as interleukin (IL)-5, IL-4, and IL-13. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation. Th2-low asthma can be mediated by non-Th2 cytokines, including IL-17 and tumor necrosis factor-α. There is emerging evidence to demonstrate that inflammation-independent processes also contribute to asthma pathogenesis. […] The pathological mechanisms of asthma are complex, varying in different phenotypes caused by different environmental triggers, ages, obesity, genetic factors, etc. In addition to airway inflammation, there is emerging evidence to suggest that inflammation-independent processes also contribute to asthma pathogenesis.

• #1 Biologics for the Treatment of Asthma | AAFA.org

  https://aafa.org/asthma/asthma-treatment/biologics-asthma-treatment/

  Asthma is a chronic lung disease that causes inflammation (swelling) in your airways. Swollen airways can lead to difficulty breathing, chest tightness, coughing, and wheezing. These are common asthma symptoms. They are usually treated with inhaled medicine and/or pills. […] Biologics treat your asthma by disrupting the specific cells or blocking specific molecules that make your airways swell after exposure to certain triggers. Trigger exposure causes the molecules in your immune system to work together to create swelling in your airways. Biologics attach to these molecules and prevent them from causing inflammation and symptoms. […] Eosinophilic asthma and allergic asthma are caused by type 2 inflammation. […] People with eosinophilic asthma have high levels of white blood cells called eosinophils.

• #1 FASENRA® (benralizumab) Mechanism of Action | For HCPs

  https://www.fasenrahcp.com/mechanism-of-action

  Eosinophils are key effector cells of eosinophilic asthma and are involved with multiple inflammatory pathways. […] Eosinophils are a driver of eosinophilic asthma that may increase the risk for exacerbations. […] Elevated eosinophils are key contributors to the inflammatory cascade in severe uncontrolled asthma. […] Once eosinophils are activated by cytokines, they begin to upregulate these signals, resulting in a damaging feedback loop of inflammation. […] The mechanism of action of benralizumab in asthma has not been definitively established. […] With benralizumab, eosinophils in airway tissue were shown to be REDUCED BY ~96% AFTER 84 DAYS. […] A 12-week Phase 1 trial evaluated the effect of benralizumab on eosinophil depletion in airway mucosa in adult patients with eosinophilic asthma. Patients had a 96% median reduction from baseline in airway mucosa eosinophils after treatment with benralizumab compared with a 47% reduction in the placebo group at Day 84.

• #1 The Inflammatory Response in the Pathogenesis of Asthma

  https://www.degruyter.com/document/doi/10.7556/jaoa.2011.20014/html?lang=en

  The release of histamine and prostaglandin D2 (PGD2) results in bronchoconstriction. […] Increased numbers of eosinophils are present in the airways of most patients with asthma. […] Eosinophils can present antigen to T cells and release growth factors such as TGF-highlighting the importance of eosinophils in multiple facets of asthmatic inflammation. […] T cells are now recognized to play important effector roles in patients with asthma. […] Interleukin 13 produced from Th2 cells has been the focus of much research as a therapeutic target. […] Thus, IL-13 provides an attractive therapeutic target that might be beneficial to consider in many asthma phenotypes, including steroid-insensitive asthma.

• #1 Pathophysiology Of Asthma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551579/

  The number of myofibroblasts, which give rise to collagen, will cause an increase in the epithelium, which narrows the smooth muscle layer and lamina reticularis. […] As a result, there is an increased thickening of the basement membrane. A person can have irreversible obstruction of airflow, which is believed to be due to airway remodeling. […] Remodeling occurs by epithelial cells transitioning to mesenchymal, increasing the smooth muscle content. Epithelial cells lose their cell adhesion and functional polarity with tight junctions, reformatting their cells to develop into mesenchymal cells. […] Additionally, eosinophils can further exacerbate airway remodeling due to their release of TGF-B and cytokines by interactions with mast cells. These mechanisms of airway remodeling may worsen inflammation and aggravate asthma over time if not treated and managed correctly.

• #1 Immunologic Pathophysiology and Airway Remodeling Mechanism in Severe Asthma: Focused on IgE-Mediated Pathways

  https://www.mdpi.com/2075-4418/11/1/83

  Despite the expansion of the understanding in asthma pathophysiology and the continual advances in disease management, a small subgroup of patients remains partially controlled or refractory to standard treatments. […] The underlying immunopathological mechanisms of asthma lead to chronic airway inflammation resulting in airway remodeling (AR), a process of structural changes of airway walls. […] Persistent inflammation of the airways not only causes asthma symptoms but also leads to the remodeling process. AR is a process of reconstruction of the bronchial wall, and it is characterized by (1) smooth muscle hypertrophy/ hyperplasia, (2) mucus gland hyperplasia, (3) shedding and metaplasia of the epithelium, (4) angiogenesis, (5) subepithelial collagen and glycoprotein deposition and (6) extracellular matrix (ECM) deposition in the submucosa, muscle and adventitia.

• #1 Asthma: Types, Causes, Symptoms, Diagnosis & Treatment

  https://my.clevelandclinic.org/health/diseases/6424-asthma

  Non-allergic: Outside factors can cause asthma to flare up. Exercise, stress, illness and weather may cause a flare. […] Certain respiratory infections, such as respiratory syncytial virus (RSV), can damage young childrens developing lungs. […] You can have an asthma attack if you come in contact with substances that irritate you. Healthcare providers call these substances triggers. […] Triggers can be different for each person. But some common triggers include: Air pollution: Many things outside can cause an asthma attack. […] Dust mites: You cant see these bugs, but they are in our homes. If you have a dust mite allergy, this can cause an asthma attack. […] Exercise: For some people, exercising can cause an attack. […] Mold: Damp places can spawn mold, which can cause problems if you have asthma.

• #1 Asthma: Types, Causes, Symptoms, Diagnosis & Treatment

  https://my.clevelandclinic.org/health/diseases/6424-asthma

  Tobacco smoke: If you or someone in your home smokes, you have a higher risk of developing asthma. […] The goal of asthma treatment is to control symptoms. Asthma control means you: Can do the things you want to do at work and home. […] Have no (or minimal) asthma symptoms. […] Rarely need to use your reliever medicine (rescue inhaler). […] You should keep track of your asthma symptom. Its an important piece of managing the disease. […] If your healthcare provider says you have asthma, youll need to figure out what triggers an attack. Avoiding the triggers can help you avoid an attack. […] Asthma that gets worse at night is sometimes called nighttime asthma or nocturnal asthma. […] Serious asthma attacks, and sometimes deaths, can happen at night. […] If you have asthma that is moderate-to-severe, or if your asthma symptoms arent well controlled, youre at greater risk of having to be hospitalized if you get COVID-19.

• #1 Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma – Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7223/

  Asthma is a chronic inflammatory disorder of the airways. This feature of asthma has implications for the diagnosis, management, and potential prevention of the disease. […] Airway inflammation contributes to airway hyperresponsiveness, airflow limitation, respiratory symptoms, and disease chronicity. […] In some patients, persistent changes in airway structure occur, including sub-basement fibrosis, mucus hypersecretion, injury to epithelial cells, smooth muscle hypertrophy, and angiogenesis. […] Gene-by-environment interactions are important to the expression of asthma. […] The concepts underlying asthma pathogenesis have evolved dramatically in the past 25 years and are still undergoing evaluation as various phenotypes of this disease are defined and greater insight links clinical features of asthma with genetic patterns.

• #1 Status Asthmaticus: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2129484-overview

  Status asthmaticus is an acute exacerbation of asthma that remains unresponsive to initial treatment with bronchodilators. Status asthmaticus can range from a mild form to a severe form with bronchospasm, airway inflammation, and mucus plugging that can cause difficulty breathing, carbon dioxide retention, hypoxemia, and respiratory failure. It is considered a medical emergency, requiring immediate recognition and treatment to prevent progression to respiratory failure. […] The pathophysiology of status asthmaticus can be attributed to multiple key mechanisms that collectively result in severe airflow obstruction, impaired gas exchange, and respiratory failure, necessitating aggressive and prompt medical intervention. Those mechanisms are airway inflammation and edema, mucus plugging, bronchoconstriction, ultimately leading to V/Q mismatch resulting in severe hypoxemia.

• #1 Status Asthmaticus: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2129484-overview

  Within minutes of exposure to an allergen, mast cell degranulation is observed along with the release of inflammatory mediators, including histamine, prostaglandin D2, and leukotriene C4. These substances cause airway smooth-muscle contraction, increased capillary permeability, mucus secretion, and activation of neuronal reflexes. The early asthmatic response is characterized by bronchoconstriction that is generally responsive to bronchodilators (eg, beta2-agonist agents). […] The release of inflammatory mediators primes adhesion molecules in the airway epithelium and capillary endothelium, and this priming then allows inflammatory cells (eg, eosinophils, neutrophils, and basophils) to attach to the epithelium and endothelium and subsequently migrate into the tissues of the airway. Eosinophils release eosinophilic cationic protein (ECP) and major basic protein (MBP). Both ECP and MBP induce desquamation of the airway epithelium and expose nerve endings. This interaction promotes further airway hyperresponsiveness in asthma.

• #1 Status Asthmaticus: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2129484-overview

  Bronchospasm, mucus plugging, and edema in the peripheral airways result in increased airway resistance and obstruction. Air trapping results in lung hyperinflation, ventilation/perfusion (V/Q) mismatch, and increased dead-space ventilation. The lung becomes inflated near the end-inspiratory end of the pulmonary compliance curve, with decreased compliance and increased work of breathing. […] The increased pleural and intra-alveolar pressures that result from obstruction and hyperinflation, together with the mechanical forces of the distended alveoli, eventually lead to a decrease in alveolar perfusion. The combination of atelectasis and decreased perfusion leads to V/Q mismatch within lung units. The V/Q mismatch and resultant hypoxemia trigger an increase in minute ventilation.

• #1 New mechanism to explain asthma attacks

  https://sciencemediacentre.es/en/reaction-study-proposing-new-mechanism-explain-asthma-attacks

  An international team of researchers, with Spanish participation, has proposed in the journal Science a new mechanism to explain asthma attacks more fully. According to their hypothesis, the mechanical forces that occur during these episodes cause cells to accumulate in excess, leading to a process of elimination called „cell extrusion”. As a result, the tissue is damaged, loses its barrier function and increases the risk of successive attacks. […] The study is quite interesting and of good quality. It talks about a new concept, the excess of cell extrusion due to the mechanical forces that are created. This study includes basic animal experiments where asthma is induced and shows that these mechanisms can be prevented by blocking the extrusion pathway with gadolinium or S1P inhibitors, reducing the subsequent inflammatory response.

• #1

  https://www.kcl.ac.uk/news/discover-limiting-damage-asthma-attack-could-stop-disease

  Scientists at Kings have discovered a new cause for asthma that sparks hope for treatment that could prevent the life-threatening disease. […] The new study, published today in Science, shows for the first time that many features of an asthma attack – inflammation, mucus secretion, and damage to the airway barrier that prevents infections – result from this mechanical constriction in a mouse model. […] The findings suggest that blocking a process that normally causes epithelial cell death could prevent the damage, inflammation, and mucus that result from an asthma attack. […] Without this barrier, asthma sufferers are far more likely to get long-term inflammation, wound healing, and infections that cause more attacks. […] By understanding this fundamental mechanism, we are now in a better position to prevent all these events.

• #1 How allergens trigger asthma attacks | CNRS

  https://www.cnrs.fr/en/press/how-allergens-trigger-asthma-attacks

  A team of Inserm and CNRS researchers from the Institute of Pharmacology and Structural Biologyor IPBS (CNRS / Universit Toulouse IIIPaul Sabatier)have identified a protein that acts like a sensor detecting various allergens in the respiratory tract responsible for asthma attacks. […] The IPBS team has identified a human protein that reacts to many environmental allergens: interleukin-33 (IL-33). When allergens enter the human respiratory tract, they release proteases that hack IL-33 molecules into extremely reactive pieces triggering the chain reactions behind allergy symptoms. […] IL-33 was shown to detect 14 different allergens tested, which include some present in ambient air (i.e. pollen, house dust mites, and fungal spores) and others associated with occupational asthma (like subtilisin, found in detergents).

• #1 Pathophysiology Of Asthma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551579/

  Th2 lymphocytes play an integral role where they produce a series of interleukins (IL-4, IL-5, IL-13) and GM-CSF, which aid in communication with other cells and sustain inflammation. […] Within the next several hours, the late phase occurs, in which eosinophils, basophils, neutrophils, and helper and memory T-cells all localize to the lungs as well, which perform bronchoconstriction and cause inflammation. […] It is critical to recognize both of these two mechanisms to target therapy and relieve both bronchoconstriction and inflammation, depending on the severity of the disease. […] Airway hyperresponsiveness is a crucial feature of asthma; this is an exaggerated bronchoconstrictor response, usually to different stimuli. There are a variety of mechanisms leading to airway hyperresponsiveness.

• #1 What is the pathophysiology of asthma?

  https://www.medicalnewstoday.com/articles/asthma-pathophysiology

  Once this inflammatory response develops, it causes a cascade of adverse effects on the airways. For instance, it causes the airways smooth muscle to contract, leading to bronchoconstriction. The inflammation also causes excess mucus production in the airways, possibly forming a mucus plug. […] The first step in asthma treatment involves determining the triggers and assessing the severity of symptoms and frequency of flare-ups. […] Treatment for asthma should recognize the three mechanisms that develop during an asthma attack. These include: inflammation, which leads to swelling in the airways; excess mucus production that contributes to airway obstruction; bronchoconstriction, which narrows the airways. […] The pathophysiology of asthma is how the disease affects the normal function of the airways. It includes hypersensitivity of the airways, airflow obstruction, and reversibility. […] However, in some people, if asthma remains untreated and frequent attacks develop, the inflammation can cause structural changes in the airways. Developing airway remodeling, such as thickening and stiffening of the airway smooth muscle, can further cause airflow obstruction.

• #1 Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma – Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7223/

  Central to the various phenotypic patterns of asthma is the presence of underlying airway inflammation, which is variable and has distinct but overlapping patterns that reflect different aspects of the disease, such as intermittent versus persistent or acute versus chronic manifestations. […] Acute and chronic inflammation can affect not only the airway caliber and airflow but also underlying bronchial hyperresponsiveness, which enhances susceptibility to bronchospasm. […] Treatment with anti-inflammatory drugs can, to a large extent, reverse some of these processes; however, the successful response to therapy often requires weeks to achieve and, in some situations, may be incomplete. […] For some patients, the development of chronic inflammation may be associated with permanent alterations in the airway structure referred to as airway remodeling that are not prevented by or fully responsive to currently available treatments.

• #1 Targeting cell signaling in allergic asthma | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-019-0079-0

  Asthma is chronic inflammation of the airways characterized by airway hyper-responsiveness, wheezing, cough, and dyspnea. The Th2 immune response is a major contributor to the pathophysiology of asthma. Targeted therapy modulating cell signaling pathways can be a powerful strategy to design new drugs to treat asthma. The potential molecular pathways that can be targeted include IL-4-IL-13-JAK-STAT-MAP kinases, adiponectin-iNOS-NF-B, PGD2-CRTH2, IFNs-RIG, Wnt/-catenin-FAM13A, FOXC1-miR-PI3K/AKT, JNK-Gal-7, Nrf2-ROS, Foxp3-RORt, CysLTR, AMP, Fas-FasL, PTHrP/PPAR, PAI-1, FcRI-LAT-SLP-76, Tim-3-Gal-9, TLRs-MyD88, PAR2, and Keap1/Nrf2/ARE. Therapeutic drugs can be designed to target one or more of these pathways to treat asthma. […] Bronchial inflammation, smooth muscle spasm, and mucus production in allergic asthma are triggered by IL-4, IL-5, and IL-13, which are released by Th2 cells. IL-13 plays the main role in the excessive secretion of mucus and AHR. IL-5 participates in the activation and migration of eosinophils to airways triggering bronchial inflammation. IL-4 induces IgE isotype switching in B cells and upregulates high-affinity IgE receptor (FcRI) on the surface of target cells.

• #1 Advances in the pathogenesis and personalised treatment of paediatric asthma | BMJ Medicine

  https://bmjmedicine.bmj.com/content/2/1/e000367

  The diversity of pathology of severe paediatric asthma demonstrates that the one-size-fits-all approach characterising many guidelines is inappropriate. […] Advances in the understanding of the underlying pathogenesis and the identification of clinical phenotypes and molecular endotypes has prompted a shift towards personalised treatment for children and young people with asthma. […] Healthcare professionals caring for children and young people with asthma should be aware of how to use objective measurements to make the diagnosis, and the advances in understanding of the pathogenesis of paediatric asthma that are substantially changing the management of asthma. […] The in-depth examination of the airway and identification of traits enables a better understanding of airway inflammation in asthma and identification of coexisting and alternative airway pathologies.

• #1 Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma – Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7223/

  The concept that asthma may be a continuum of these processes that can lead to moderate and severe persistent disease is of critical importance to understanding the pathogenesis, pathophysiology, and natural history of this disease. […] Inflammation has a central role in the pathophysiology of asthma. […] The processes by which these interactive events occur and lead to clinical asthma are still under investigation. […] The pattern of airway inflammation in asthma, however, does not necessarily vary depending upon disease severity, persistence, and duration of disease. […] The mechanisms influencing airway hyperresponsiveness are multiple and include inflammation, dysfunctional neuroregulation, and structural changes; inflammation appears to be a major factor in determining the degree of airway hyperresponsiveness.

• #2 Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma – Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7223/

  Asthma is a chronic inflammatory disorder of the airways. This feature of asthma has implications for the diagnosis, management, and potential prevention of the disease. […] Airway inflammation contributes to airway hyperresponsiveness, airflow limitation, respiratory symptoms, and disease chronicity. […] In some patients, persistent changes in airway structure occur, including sub-basement fibrosis, mucus hypersecretion, injury to epithelial cells, smooth muscle hypertrophy, and angiogenesis. […] Gene-by-environment interactions are important to the expression of asthma. […] The concepts underlying asthma pathogenesis have evolved dramatically in the past 25 years and are still undergoing evaluation as various phenotypes of this disease are defined and greater insight links clinical features of asthma with genetic patterns.

• #2 Asthma: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/296301-overview

  Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness, which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma, airflow limitation may be only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and subepithelial fibrosis) that occurs with chronic untreated disease. […] Airflow obstruction can be caused by a variety of changes, including acute bronchoconstriction, airway edema, chronic mucous plug formation, and airway remodeling. Acute bronchoconstriction is the consequence of immunoglobulin E-dependent mediator release upon exposure to aeroallergens and is the primary component of the early asthmatic response. Airway edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic response. Chronic mucous plug formation consists of an exudate of serum proteins and cell debris that may take weeks to resolve. Airway remodeling is associated with structural changes due to long-standing inflammation and may profoundly affect the extent of reversibility of airway obstruction.

• #2 Pathophysiology Of Asthma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551579/

  Th2 lymphocytes play an integral role where they produce a series of interleukins (IL-4, IL-5, IL-13) and GM-CSF, which aid in communication with other cells and sustain inflammation. […] Within the next several hours, the late phase occurs, in which eosinophils, basophils, neutrophils, and helper and memory T-cells all localize to the lungs as well, which perform bronchoconstriction and cause inflammation. […] It is critical to recognize both of these two mechanisms to target therapy and relieve both bronchoconstriction and inflammation, depending on the severity of the disease. […] Airway hyperresponsiveness is a crucial feature of asthma; this is an exaggerated bronchoconstrictor response, usually to different stimuli. There are a variety of mechanisms leading to airway hyperresponsiveness.

• #2 Asthma attack – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/asthma-attack/symptoms-causes/syc-20354268

  An asthma attack is a sudden worsening of asthma symptoms. Asthma is a long-term condition that makes breathing difficult because airways in the lungs become narrow. […] These symptoms happen because muscles around airways tighten up, the airways become irritated and swollen, and the lining of the airways produces a fluid called mucus. All of these factors make it difficult to breathe. […] Asthma is usually a lifelong disease of inflammation in the lungs caused by an overactive immune system. Inflammation in the lungs includes the tightening of muscles around airways, swelling of tissues in the airways and the release of mucus that can block airways. When this happens, it’s difficult to breathe. […] Asthma attacks occur when something triggers the immune system to take action. Triggers may include: Allergic reaction to pollen, pets, mold, cockroaches and dust mites. Colds, the flu or other illnesses affecting the nose, mouth and throat. Tobacco smoke. Cold, dry air. Exercise. A condition called gastroesophageal reflux disease (GERD) that results in stomach acids entering the tube between the mouth and stomach. Pollution or irritating chemicals in the air. Pain relievers, such as aspirin and nonsteroidal anti-inflammatories, and some other medicines. Depression or anxiety. […] Severe asthma attacks can cause death. Life-threatening asthma attacks are more likely for people who frequently use quick-relief medicines, have had emergency room visits or hospital stays to treat asthma, or have other long-term illnesses.

• #2 Video: Asthma: Pathogenesis and Management

  https://www.jove.com/science-education/v/15228/asthma-pathogenesis-and-management

  Following this immediate reaction, a late-phase response occurs several hours later. It involves the influx of eosinophils and lymphocytes into the airways, releasing inflammatory proteins called interleukins. This response sustains the bronchoconstriction, inflammation, and mucus production, contributing to the chronic nature of asthma. […] In non-allergic asthma, the pathogenesis differs as it is not driven by allergens or an IgE-mediated immune response. Instead, it involves airway hyper-responsiveness to non-immune triggers, such as cold air, exercise, air pollutants, respiratory infections, or strong emotions. These triggers lead to direct activation of bronchial smooth muscles and epithelial cells, causing the release of inflammatory mediators like histamine and leukotrienes. This inflammatory response contributes to bronchoconstriction, airway inflammation, and mucus production, similar to allergic asthma.

• #2 The Inflammatory Response in the Pathogenesis of Asthma

  https://www.degruyter.com/document/doi/10.7556/jaoa.2011.20014/html?lang=en

  The respiratory epithelium is an integral part of innate immunity and the inflammatory response, and it is capable of producing numerous mediators that can prime and activate many arms of the immune system. […] The airway epithelium produces large amounts of inflammatory cytokines, including TNF-, IL-1, and IL-6. […] Chemokines play an important role in the recruitment of inflammatory cells from circulation to the airways. […] The epithelium also releases growth factors that augment the inflammatory response and induce structural changes and remodeling of the airways. […] The central component of allergic asthma is the development of an immunoglobulin E (IgE) antibody-mediated response to allergens that requires the interaction of a number of leukocytes. […] Binding of allergen to IgE on the cell surface induces a signal transduction cascade that results in the release of mediators.

• #2 The Inflammatory Response in the Pathogenesis of Asthma

  https://www.degruyterbrill.com/document/doi/10.7556/jaoa.2011.20014/html?lang=en&srsltid=AfmBOopxpev5zIpMQFpuD0rlrxJaZlFnnUOkuEw61BOH7g2ng0jV_u2s

  The release of histamine and prostaglandin D2 (PGD2) results in bronchoconstriction. […] Increased numbers of eosinophils are present in the airways of most patients with asthma. […] The recruitment, growth, and survival of eosinophils are promoted by factors released from airway epithelial cells, Th2 cells, and mast cells. […] Eosinophils express a variety of proinflammatory cytokines, Th2 cytokines, and chemokines that can activate mast cells and stimulate the epithelium. […] The role of eosinophils in asthma may vary with different phenotypes, and patients with severe asthma are noted to have elevated numbers of eosinophils. […] T cells are now recognized to play important effector roles in patients with asthma. […] Interleukin 13 produced from Th2 cells has been the focus of much research as a therapeutic target.

• #2 Current Understanding of Asthma Pathogenesis and Biomarkers

  https://www.mdpi.com/2073-4409/11/17/2764

  Recent studies demonstrated that the airway epithelium produces cytokines in response to injury, infection, and pollutants. These epithelial-derived cytokines include thymic stromal lymphopoietin (TSLP), IL-25, and IL-33. TSLP, IL-25, and IL-33 activate type 2 innate lymphoid cells (ILC2), which generate Th2 cytokines, such as IL-5 and IL-13 and induce Th2 lung inflammation. […] IL-17 has been proposed to play an important role in Th2-low asthma. Higher levels of IL-17 are found in serum, sputum, and bronchoalveolar lavage fluid (BALF) of patients with asthma, which is associated with asthma severity. IL-17 cytokines may stimulate epithelial cells and fibroblasts to release neutrophil chemoattractants CXCL1/5/8 and granulocyte–macrophage colony-stimulating factor, which recruit neutrophils to the lungs. Furthermore, IL-17A, but not IL-17F, enhances airway smooth muscle contraction, migration, and proliferation, which facilitates airway hyperresponsiveness (AHR) and airway remodeling, key characteristics of asthma.

• #2 Biologics for the Treatment of Asthma | AAFA.org

  https://aafa.org/asthma/asthma-treatment/biologics-asthma-treatment/

  People with allergic asthma have an overly active immune response to common allergens, like dust or pollen. […] Eosinophilic and allergic asthma can overlap. If you have severe allergic asthma, it is likely you also have high levels of eosinophils. […] Non-type-2 asthma is also called non-eosinophilic asthma. Eosinophils are not present in the airway. Different types of white blood cells build up and cause inflammation. […] Six biologics currently are approved by the FDA for moderate-to-severe asthma. Xolair is approved for allergic asthma. Nucala, Fasenra, and Cinqair are approved for eosinophilic asthma. Dupixent may work for type 2 asthma more broadly (allergic and eosinophilic). Tezspire may work for all types of asthma. Tezspire is the only biologic approved for non-type-2 asthma.

• #2 Immunological factors, important players in the development of asthma | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00644-w

  The balance between the immune response of Th cells and the immunosuppression of Tregs is important for the maintenance of immune homeostasis. […] Eosinophils play a pivotal role in asthma, as their accumulation in lung tissue is stimulated by IL-5, thereby fostering eosinophil formation in the bone marrow and attracting eosinophils to the lung mucosa and mesenchyme via eosinophil chemokines (e.g., eotaxins). […] Elevated serum IgE levels are a crucial indicator for patient assessment and strongly correlate with asthma development.

• #2 Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma – Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7223/

  Airway remodeling involves an activation of many of the structural cells, with consequent permanent changes in the airway that increase airflow obstruction and airway responsiveness and render the patient less responsive to therapy. […] The development of monoclonal antibodies against IgE has shown that the reduction of IgE is effective in asthma treatment. […] Recent scientific investigations have focused on translating the increased understanding of the inflammatory processes in asthma into therapies targeted at interrupting these processes. […] Our understanding of asthma pathogenesis and underlying mechanisms now includes the concept that gene-by-environmental interactions are critical factors in the development of airway inflammation and eventual alteration in the pulmonary physiology that is characteristic of clinical asthma.

• #2 Immunologic Pathophysiology and Airway Remodeling Mechanism in Severe Asthma: Focused on IgE-Mediated Pathways

  https://www.mdpi.com/2075-4418/11/1/83

  The pleiotropic effects of IgE are mediated by activation of specific IgE receptors expressed by both immune-inflammatory (mast cells, eosinophils, basophils and dendritic cells) and airway structural cells (airway epithelium cells and airway smooth muscle cells (ASMCs)). […] Recent studies suggested that ASMCs responded to both IgE and cytokinergic IgE by increased proliferation, ECM production and collagen deposition. […] The signaling pathway activated by allergen-bonded IgE consist of phosphatidylinositol 3-kinases (PI3K) -> protein kinase B (Akt) -> mammalian target of rapamycin (mTOR) signaling. […] As a result of AR, asthma patients, who have persistent chronic airway inflammation, may experience airway obstruction, which leads to worsening lung function, symptoms and response to bronchodilators.

• #2 Asthma: pathophysiology, causes and diagnosis – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/asthma-pathophysiology-causes-and-diagnosis

  If an attack is left untreated, eosinophils, T-helper cells and mast cells migrate into the airways. Excess mucus production caused by goblet cells plug the airway and, together with increased airway tone and airway hyperresponsiveness, this causes the airway to narrow and further exacerbates symptoms. […] There is some evidence to suggest that airway remodelling can occur if asthma is poorly controlled over a period of years. Chronic inflammation causes bronchial smooth muscle hypertrophy, the formation of new vessels and interstitial collagen deposition, which results in persistent airflow obstruction similar to that seen in patients with chronic obstructive pulmonary disease (COPD).

• #2

  https://www.kcl.ac.uk/news/discover-limiting-damage-asthma-attack-could-stop-disease

  Scientists at Kings have discovered a new cause for asthma that sparks hope for treatment that could prevent the life-threatening disease. […] The new study, published today in Science, shows for the first time that many features of an asthma attack – inflammation, mucus secretion, and damage to the airway barrier that prevents infections – result from this mechanical constriction in a mouse model. […] The findings suggest that blocking a process that normally causes epithelial cell death could prevent the damage, inflammation, and mucus that result from an asthma attack. […] Without this barrier, asthma sufferers are far more likely to get long-term inflammation, wound healing, and infections that cause more attacks. […] By understanding this fundamental mechanism, we are now in a better position to prevent all these events.

• #2

  https://www.kcl.ac.uk/news/discover-limiting-damage-asthma-attack-could-stop-disease

  The answer to stopping asthma symptoms may lie in cell extrusion, a process the researchers discovered that drives most epithelial cell death. […] Because bronchoconstriction causes so many cell extrusions, it damages the airway barrier which causes inflammation and excess mucus. […] This constriction and destruction of the airways causes the post-attack inflammation and excess mucus secretion that makes it difficult for people with asthma to breathe. […] Current therapies do not prevent this destruction – an inhaler such as Albuterol opens the airways, which is critical to breathing but, dishearteningly, we found it does not prevent the damage and the symptoms that follow an attack. […] This study identifies a new process known as epithelial extrusion whereby damage to the lining of the airway occurs as a consequence of mechanical constriction and can drive many of the key features of asthma.

• #2 How allergens trigger asthma attacks | CNRS

  https://www.cnrs.fr/en/press/how-allergens-trigger-asthma-attacks

  Indeed, the gene that codes for IL-33 is among the principal ones predisposing humans to asthma. […] Inhibiting production of reactive IL-33 fragments after allergen exposure might make it possible to limit severe allergic reactions in asthmatic patients. […] The IL-33 protein, a major factor predisposing humans to asthma, detects allergen protease activity. Activated by proteases, IL-33 sets off a cascade of reactions, including mucus production, that are associated with asthma and other allergic diseases. When IL-33 activation is inhibited, these reactions are not triggered.

• #2 Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma – Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7223/

  Central to the various phenotypic patterns of asthma is the presence of underlying airway inflammation, which is variable and has distinct but overlapping patterns that reflect different aspects of the disease, such as intermittent versus persistent or acute versus chronic manifestations. […] Acute and chronic inflammation can affect not only the airway caliber and airflow but also underlying bronchial hyperresponsiveness, which enhances susceptibility to bronchospasm. […] Treatment with anti-inflammatory drugs can, to a large extent, reverse some of these processes; however, the successful response to therapy often requires weeks to achieve and, in some situations, may be incomplete. […] For some patients, the development of chronic inflammation may be associated with permanent alterations in the airway structure referred to as airway remodeling that are not prevented by or fully responsive to currently available treatments.

• #2 Targeting cell signaling in allergic asthma | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-019-0079-0

  The IL-4/IL-13/STAT-6 pathway is a key modulator of asthma pathophysiology. The activation of STAT-6 can be blocked by interfering with the interaction of STAT-6-MAP kinase with ERK1/2 and p38, as well as by suppressing STAT-6 serine phosphorylation, preventing STAT-6 acetylation, and inhibiting the recruitment of the p300 transcriptional coactivator. […] Several therapeutics have been introduced to interfere with the IL-4/IL-13/JAK/STAT-6 pathway. These include inhibitors of JAK, dimerization suppressors, phosphopeptides targeting the SH2 domain of STAT-6, decoy oligonucleotides, siRNAs, and finally synthetic small molecules. […] The activation of the DP2 receptor on Th2 cells upregulates the expression of IL-4, IL-5, and IL-13 in a dose-dependent manner and induces Th2 migration. DP2 activation on eosinophils, on the other hand, facilitates the migration of these cells and increases eosinophil degranulation.

• #2 Biologics for the Treatment of Asthma | AAFA.org

  https://aafa.org/asthma/asthma-treatment/biologics-asthma-treatment/

  Biomarkers can help identify what kind of asthma you have. […] Your asthma may be uncontrolled if: You have asthma symptoms more than two times a week; You wake up at night with asthma symptoms more than two times a month; You need your reliever inhaler for symptoms more than two times a week; You need to take oral corticosteroids more than one time a year; You are not able to do all your usual activities. […] Biologics are an add-on treatment. This means your doctor may have you take them with your routine asthma controller medicine, like an inhaled corticosteroid. Over time, you may be able to reduce your inhaled corticosteroid use or stop taking it altogether. Asthma biologics do not replace quick-relief medicines, such as albuterol. […] There are many potential benefits of using a biologic to treat your asthma. They include: Fewer asthma episodes and symptoms; Fewer asthma-related trips to the hospital or emergency room; Decreased use of oral corticosteroids (like prednisone); Lower dosage of other controller medicines (if recommended by your doctor); Improved lung function. […] Common side effects of biologics include: Headache; Reaction where the biologic is injected; Sore throat; Tiredness (fatigue); Joint pain; Skin rash. […] In rare cases, biologics can also cause a serious allergic reaction called anaphylaxis.

• #2 Advances in the pathogenesis and personalised treatment of paediatric asthma | BMJ Medicine

  https://bmjmedicine.bmj.com/content/2/1/e000367

  Severe asthma in children is often but not invariably associated with persistent eosinophilic airway inflammation, which might be relatively resistant to treatment with ICS and persist despite reduced levels of type 2 cytokines. […] The absence of these cytokines with persistent eosinophilia in severe, treatment resistant asthma has led to the hypothesis that innate mediators such as IL33, which appear to be relatively steroid resistant, could dominate the immune response in severe, treatment resistant asthma. […] In summary, not all paediatric severe asthma is driven by type 2 inflammation or will respond to anti-IL5 strategies. Critically determining what is driving the airway pathology is key to personalising treatment.

• #3 Current Understanding of Asthma Pathogenesis and Biomarkers

  https://www.mdpi.com/2073-4409/11/17/2764

  Th2 cells are a distinct lineage of CD4+ effector T cells that secrete interleukin (IL)-4, IL-5, IL-13, and IL-9. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation. Th2 inflammation has two major phases: 1. Sensitization: When allergens enter the low airways, antigen-presenting cells process and present the allergens to Th2 cells, which secret Th2 cytokines, including IL-5, IL-4, and IL-13. 2. Challenge: When the same allergens enter the airways, they bind to IgE, which induces mast cells to release mediators, such as leukotrienes (LTs), histamine, and ILs. In addition, allergens act on cholinergic nerves to release acetylcholine. These mediators and neurotransmitters irritate airway smooth muscle and induce bronchoconstriction.

• #3 Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma – Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7223/

  The concept that asthma may be a continuum of these processes that can lead to moderate and severe persistent disease is of critical importance to understanding the pathogenesis, pathophysiology, and natural history of this disease. […] Inflammation has a central role in the pathophysiology of asthma. […] The processes by which these interactive events occur and lead to clinical asthma are still under investigation. […] The pattern of airway inflammation in asthma, however, does not necessarily vary depending upon disease severity, persistence, and duration of disease. […] The mechanisms influencing airway hyperresponsiveness are multiple and include inflammation, dysfunctional neuroregulation, and structural changes; inflammation appears to be a major factor in determining the degree of airway hyperresponsiveness.

• #3 Immunological factors, important players in the development of asthma | BMC Immunology | Full Text

  https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00644-w

  Asthma is a heterogeneous disease, and its development is the result of a combination of factors, including genetic factors, environmental factors, immune dysfunction and other factors. Its specific mechanism has not yet been fully investigated. […] Immunological disorders play an important role in asthma. […] Recent studies have shown that T-cell subsets such as Th1 cells, Th2 cells, Th17 cells, Tregs and their cytokines contribute to asthma through different mechanisms. […] T helper type 1 (Th1) cells and Th2 cells are important effector cells that inhibit each other during the development of asthma. […] Th1 cells mainly mediate the cellular immune response, delay hypersensitivity and assist in the synthesis of phagocytosis-related antibodies, e.g., IgG, IgM and IgA, which may inhibit the development of asthma.

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