See also Mast cells (immune cells) and basophils (granulocytes)
Introduction:
Airway diseases include diseases which effect the respiratory tract (e.g., lungs, mouth, nose, pulmonary, alveoli, pharynx, larynx, trachca, and bronchi). Airway diseases, such as asthma and COPD are a major health burden in the developed world.
Asthma:
Asthma is a respiratory disease characterized by episodes of impaired breathing due to severe bronchoconstriction. The airways of asthmatic people are very responsive to minute amounts of inhalants, ingestant or other stimuli, such as infectious agents. The symptoms range from occasional, annoying bouts of difficult breathing to faal suffocation. The respiratory tract is chronically inflamed and sverely overreactive to allergic mediators, especially leukotrienes and serotonin from pulmonary mast cells.
Pathology:
Under the guidance of locally released chemokines, many inflammatory cells are recruited to the lungs from the bloodstream; these cells exert functional properties for asthma development. Furthermore, airway structural cells, including epithelial cells, fibroblasts, and airway smooth muscle cells (SMCs), are essential inflammatory mediator sources that actively participate in the inflammatory process. In individuals with asthma, both innate (mast cells, DCs, eosinophils, neutrophils, basophils, ILCs, monocytes, and macrophages) and adaptive (T and B lymphocytes) immunities are involved in the inflammatory cell profile. See Gao
It is well-known that TH2 cells orchestrate eosinophilic airway inflammation by producing abundant amounts of IL-4, IL-5, and IL-13. IL-4 is required for allergic sensitization and IgE class switching, IL-5 is warranted for eosinophil survival, IL-13 exerts multifunctional effects in the lungs, including a vital role in controlling mucus production, goblet cell metaplasia, bronchial hyperresponsiveness, and airway remodeling. In contrast, TH1 cells release IL-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, possibly conferring a protective role in asthma because they can directly antagonize pathologic TH2 responses to control eosinophilic inflammation. To support this, IL-12, a pro-TH1 cell cytokine, administration in mice suppresses antigen-induced airway hyperresponsiveness and inflammation by producing IFN-γ via TH1 cells. However, recent studies on the phenotype of type 2-low asthma have demonstrated the dominance of IFN-γ+TH1 cells in severe disease forms, which is potentially associated with corticosteroid refractoriness. See Gao
In addition to TH2 cells, TH17 cells and their produced cytokine IL-17A are prominent and extensively studied in the context of asthma, particularly in severe, steroid-resistant cases. These TH17-derived cytokines, including IL-17 and IL-22, are related to increased neutrophil recruitment in the airways. To this end, neutrophil extracellular traps and cytoplasts further promote TH17 polarization and neutrophilic inflammation in severe asthma. However, the precise roles of TH17 cells and IL-17 in mouse asthma models remain unknown primarily because IL-17 may play dual regulatory roles: it plays a protective role in the challenge stage but worsens asthma under other conditions. See Gao
ncreasing evidence in animals indicates that a major hallmark of several autoimmune disorders, including asthma, is functional defects in Tregs. In a broader perspective, as a diverse population, Tregs comprise CD4+CD25+ forkhead box (Fox)p3+ natural and inducible Tregs, IL-10-producing Tr1 cells, transforming growth factor (TGF)-β-producing TH3 cells, and other minor subsets with suppressive functions, including CD4−CD8− T and γδT cells. See Gao
Treatment:
–Antibodies:
—-IL4 & IL-13: Dupilumab, sold under the brand name Dupixent (Sanofi & Regeneron –over 15 billion in sales 2024), is a monoclonal antibody blocking interleukin 4 and interleukin 13 receptor signalling, used for allergic diseases such as atopic dermatitis, asthma and nasal polyps which result in chronic sinusitis.
—-OX-40: Rocatinlimab (Amgen) is a mAb that inhibits OX-40. It is being investigated in Phase 3 studies for teh tereamtent of moderate to severe atopic dermatitis and prurigo nodularis. It is also being investigated in a phase 2 study for the treatment of moderate to severe asthma.
—-TSLP: AMG 104 (Amgen) is an anti-TSLP Fab that is being investigated for the treatment of asthma in collaboration with Astra Zeneca.
Airway hyperresponsiveness (AHR):
AHR is an exaggerated airway constrictive response to external triggers and is a major component of airway disease. AHR is a hallmark of asthma, but also occurs in many other airway diseases such as COPD. AHR is also known as bronchial hyperresponsiveness or airway hyperreactivity. Current treatment is non-specific and consists of bronchodilators (adrenergic or anticholigergiv) and immunosuppressants (corticosteroids).
Chronic Obstructive Pulmonary Disease (COPD) (e.g., Asthma): see outline
Cystic fibrosis (CF):
CF is a hereditary (autosomal recessive) disease affecting the exocrine (mucus) glands of the lungs, liver, pancrease, and intestines, causing progressive disability due to multisystem failure. CF is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator. The product of thse gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. Thick mucus production in CF patients results in fequent lung infections. Lung disease results from clogging the airways due to mucosa buildup and resulting inflammation.
Refractory Chronic Cough (RCC):
Chronic cough affects about 28 million people and around 10 million suffer form RCC for over a year. RCC is a cough that lasts for more than 8 weeks, does not resond to treatmnet for an underlying condition and is otherwise unexplained. There is currently no effective treatment, with patients often cycling through other therapies and seeing specialists with no resolution.
Treatment:
–Inhibiting P2X3 Receptors:
—–Camplipixant (GlaxoSmith):
P2X3 is a validated biological target implicated in cough reflex hypersensitisation, and camlipixant is a highly selective P2X3 antagonist. Current clinical data show that by selectively inhibiting P2X3 receptors, camlipixant may reduce cough frequency for patients suffering from RCC with a relatively low incidence of dysgeusia, the taste disturbance adverse event associated with other medicines that broadly target the P2X2/3 receptor.