Review: 【Pathology】Pathophysiology of severe asthma: We’ve only just started part 1
Content:
2. Asthma
3. Asthma 的pathophysiology点在于？
4. AIRWAY REMODELLING: THE SIMPLE AIRWAY TUBE MODEL
5. AIRWAY REMODELLING: THE COMPLEX BRANCHING SYSTEM
6. REMODELLING IN SEVERE ASTHMA (Part 1)
7. FIXED AIRFLOW OBSTRUCTION IN SEVERE ASTHMA
8. THE NATURE OF THE RELATIONSHIP BETWEEN INFLAMMATION AND REMODELLING
9. INFLAMMATION HETEROGENEITY IN SEVERE ASTHMA
10. ALLERGIC AIRWAY INFLAMMATION IN SEVERE ASTHMA
11. Summary of the main points of pathophysiology in severe asthma
7. FIXED AIRFLOW OBSTRUCTION IN SEVERE ASTHMA
- Fixed reduction in lung function is highly variable between asthmatic individuals.
- increased rate of forced expiratory volume in 1 s (FEV1) loss ---不是全部患者都有
- Reduced lung function
- related to asthma severity
- tracks from infancy and childhood into adult life.
- In severe asthma, risk factors for loss of FEV1 are exacerbations
- sputum eosinophilia
- adult-onset disease
- longer duration of asthma
- AHR
- mucus hypersecretion
- blood eosinophilia
- bronchial wall thickening
- sputum neutrophilia
In a longitudinal study, the age-adjusted FEV1 decline was increased in up to 15% of severe asthmatic individuals, compared with around 2% in the general asthmatic population.
Childhood-onset asthma
- Airflow obstruction has a developmental origin that likely starts in utero, as reticular basement membrane (RBM) thickening and inflammation are present in wheezy infants and ASM remodelling has been observed in preschool children who later develop asthma.
- A number of birth cohorts have shown abnormal lung function in infants who later develop asthma.
- These changes are observed before the onset of allergic sensitization, the greatest risk factor for childhood-onset asthma.
- Thus, remodelling and inflammation may be parallel processes that may independently contribute to asthma.
- Persistence or acceleration of both inflammation and remodelling in early childhood, which are then modified by childhood exposures such as viruses and diet, could underlie the development of severe asthma and its persistence into adulthood.
- Adequate control of symptoms is not a guarantee of protection against loss of lung function
8. THE NATURE OF THE RELATIONSHIP BETWEEN INFLAMMATION AND REMODELLING
- How airway inflammation and remodelling relate to each other is uncertain.
- The traditional paradigm that
- airway inflammation drives airway remodelling
- leading to AHR
- fixed airflow obstruction
- derives from the relation of persistent eosinophilic inflammation and decreased FEV1 and from cross-sectional studies.
- Sputum neutrophilia is also an independent risk factor for reduced lung function.
- Eosinophilic, but not neutrophilic, inflammation is strongly regionally associated with increased ASM within the bronchial tree.
- The drivers of inflammation could be IgE- or IgG-mediated sensitization to aeroallergens or small molecules, abnormal epithelial repair and/or epithelial mesenchymal transformation.
Alternately, inflammation and remodelling may be complementary processes, rather than being cause and effect. 或者为互补关系，不是因果关系
The relationships between ASM remodelling and reduced FEV1, to clinical severity but not duration,
suggests an early and perhaps preexisting abnormality of airway structure that strongly influences severity but which requires inflammation to manifest clinically.
ASM 重塑和 FEV1 降低与临床严重程度而非持续时间之间的关系，提示气道结构的早期和可能预先存在的异常严重影响严重程度，但需要炎症在临床上表现出来。
This may explain the ability of antiinflammatory treatments to reverse asthma symptoms and variable airflow limitation without reversing fixed airflow limitation or altering the rate of decline of lung function.
这可能解释了抗炎治疗能够逆转哮喘症状和可变气流受限而不逆转固定气流受限或改变肺功能下降速度的能力。
Altered airway structure may itself stimulate inflammation.
Remodelling involves degradation and repair of ECM and proliferation of fibroblasts and myofibroblasts.
The action of matrix metalloproteinases on ECM releases bioactive fragments that are pro-inflammatory and increase neo-vascularization.
For example, elastin fragments have a wide range of effects and are proproliferative and pro-inflammatory and further stimulate matrix degradation via stimulating matrix metalloproteinase release.
Decreased collagen IV in asthmatic airways
- reduces the level of one of its bioactive fragments, tumstatin, in airway fluid and airway biopsies.
- Tumstatin inhibits vascularization and prevents angiogenesis, AHR, inflammatory cell infiltrate and mucus secretion in a mouse model of asthma.
- ASM cells from asthmatic individuals have proproliferative activity and increased chemotactic activity for mast cells
9. INFLAMMATION HETEROGENEITY IN SEVERE ASTHMA
A cluster analysis based on symptom control and sputum eosinophilia to group statistically similar individuals together was applied to a UK asthmatic cohort with a wide range of disease severity and age of onset
4 clusters:
a. childhood-onset asthma
associated with atopy and active airway eosinophilia whose symptoms and sputum eosinophilia were concordant.
Other 3 clusters are symptoms and sputum eosinophilia were discordant.👇👇
b. late-onset asthma
- had eosinophilia
- with few symptoms
c. obesity, late-onset disease and female gender
- non-eosinophilic
d. early-onset disease and atopy
non-eosinophilic
Another cluster analysis of 378 adult asthmatic patients enriched with severe disease from the Severe Asthma Research Programme (SARP)77 identified 112 variables including those from bronchial lavage and biopsy.
- identified by using only FEV1 and age of onset of asthma reinforces the importance and clinical utility of lung function in severe asthma.
6 clusters
- three containing severe asthmatic patients
- early-onset allergic asthma with low lung function and eosinophilic inflammation
- later-onset, mostly severe asthma with nasal polyps and eosinophilia
- those with persistent inflammation in blood and bronchoalveolar lavage (BAL) fluid and exacerbations despite high systemic corticosteroid use.
Interestingly, both the cluster analysis of severe asthma77 and general population cluster analyses identified a subgroup of overweight females likely to have severe asthma or be labelled as having asthma.
10. ALLERGIC AIRWAY INFLAMMATION IN SEVERE ASTHMA
Endobronchial biopsy of proximal airways in severe asthma
- has shown persistent type 2 inflammation
- characterized by airway eosinophils, lymphocytes, mast cells and associated thickening of the RBM
- despite regular use of oral corticosteroids.
Eosinophilia in severe asthma was similar to that in steroidnaïve, mild asthma with a tendency to increased airway neutrophils and half had no eosinophilic inflammation. 重度哮喘患者的嗜酸性粒细胞增多与未使用类固醇的轻度哮喘相似，有增加气道中性粒细胞的趋势，一半没有嗜酸性粒细胞炎症。
In a study of 80 subjects with severe asthma,
asthma onset before 12 years of age was associated with atopy (98% vs 76%),
- higher serum IgE
- increased eosinophils, lymphocytes and mast cells in the airway wall
compared with onset after 12 years.
In those with later-onset asthma, half had
- no airway eosinophilia
- tended to have lower lung function
- a history of near-fatal attacks.
Type 2 inflammation
- increased sputum eosinophils
- exhaled nitric oxide
- blood eosinophils, IgE and serum periostin with more atopy and AHR
Activation of type 2 airway inflammation in the context of severe asthma
- IL-13 upregulates airway epithelial genes such as periostin and induces mucus production.
- release mediators such as thymic stromal lymphopoietin (TSLP), activate dendritic cells
- promote the development of TH-2 lymphocytes
- IL-33 activate the inflammasome and exacerbate allergic inflammation.
- Elevated levels of IL-5 are associated airway eosinophilia and epithelial changes
- this associated with increased expression of eotaxin and inducible nitric oxide (iNOS).
- Release of IL-4
- promotes the plasma/B cell isotype switch to produce IgE
- This is associated with increased intraepithelial mast cell expression of IgE making them prone to degranulation following IgE crosslinking.
Innate lymphoid cells (ILCs) are a particular feature of severe asthma
- explain eosinophilic/type 2 inflammation that occurs independent of allergic sensitization
Increased intraepithelial mast cells in severe asthma demonstrate an altered phenotype with increased expression of chymase and tryptase.
Mast cell-derived prostaglandin D2 (PGD2) is increased
- activates both mast cells themselves as well as ILC2 cells.
- The ability to switch off inflammation may be impaired.
Reduced levels of lipoxin A4
- reduce activation of natural killer (NK) cells
- it play a crucial role in the induction of apoptosis in eosinophils and neutrophils.
11. Summary of the main points of pathophysiology in severe asthma
Airway inflammation
1. Highly heterogeneous and complex in type; impacts clinical manifestation of asthma and treatment responses
2. Both innate and adaptive immunities may be involved to explain steroid resistance
3. Eosinophilic (type 2) inflammation accounts for only approximately 50% of severe asthma
4. The complex interactions between inflammation and remodelling likely explain abnormal lung mechanics, but the mechanisms are poorly understood
Airway remodelling
1. Airway remodelling is more severe in severe asthma
2. Its distribution is heterogeneous and associated with eosinophils
3. Inflammation could cause or drive airway remodelling but the reverse could also be easily true—the interaction remains unclear
Airway and lung mechanics
1. Severe asthma is characterized by greater ventilation heterogeneity and airway closure, which involves both small and large airways
2. Abnormal lung parenchyma and adventitial attachments may worsen AHR and partly explain irreversible airway obstruction
3. There are complex mechanical interactions between small and large airways, which in turn interact with airway inflammation that may be important in explaining symptoms and AHR in severe asthma
4. There are likely strong influences in early life, with ageing and with co-morbidities such as obesity
Comments
Post a Comment