【Pathology】Pathophysiology of severe asthma: We’ve only just started part 1

Pathophysiology of severe asthma

Content:

1. Pathophysiology?
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

1. Pathophysiology?

The key to improving targeted treatments, reducing disease burden and improving patient outcomes is a better understanding of the pathophysiology and mechanisms of severe disease.

2. Asthma

Asthma is a complex interplay between airway inflammation and airway remodelling which results in airway hyperresponsiveness (AHR)—variable and excessive airway narrowing.

Severe asthma is also often associated with some degree of fixed airflow limitation

The marked thickening of the airway wall and widespread inflammatory infiltrate in severe asthma are contrasted with a similar-sized normal airway.

These pathological changes result in reduced baseline lung function (in some cases) and severe, excessive airway narrowing when the smooth muscle is stimulated to contract, compared with normal airways or mild asthma where narrowing of the airways is limited.

* histamines cause bronchoconstriction

3. Asthma 的pathophysiology点在于？

The aim of investigating asthma pathophysiology is to understand the basis of airway hyperresponsiveness (AHR) as well as incompletely reversible airflow obstruction.

了解气道高反应性 (AHR) 以及不完全可逆气流阻塞的基础

The current pathophysiological paradigm invokes remodelling, the sum of structural changes to the airway wall and lung parenchyma, to explain AHR and fixed airflow obstruction.

病理生理学: 气道壁和肺实质结构变化的总和，以解释 AHR 和固定气流阻塞

4. AIRWAY REMODELLING: THE SIMPLE AIRWAY TUBE MODEL

Normal/介绍

The airway can be conceptualized as a simple elastic ‘tube’ embedded within elastic lung parenchyma. The elastic airways stretch (dilate) as the lung stretches, due to parenchymal tethering to the airway adventitia.

In health, the elastic properties (compliance) of the lung parenchyma and airways are well matched (relative hysteresis), which underlies the relationship between lung volume and airway calibre. 肺实质和气道的弹性特性（顺应性）非常匹配（相对滞后），这是肺容量和气道口径之间关系的基础

Therefore, changes in both the mechanical properties of the lung parenchyma and its attachments to the airway wall may contribute to AHR and fixed airflow obstruction.

病变

ASM 层的厚度增加与哮喘中最大气道狭窄的增加有关

The airway walls are clearly thickened in asthma 管道小

Increased airway wall thickness contributes to airway narrowing during airway smooth muscle (ASM) contraction via geometric effects 增加阻力

Thickening of the mucosal layer and the ASM potentiates the increase in airway resistance for any given amount of ASM shortening, because airway resistance is a function of radius (of the lumen) to the fourth power. 

Thickening of the airway wall outside of the ASM decreases the elastic pull of the attached lung (the springs are slackened), thereby reducing the force against which the ASM has to shorten. 降低弹性（减少收缩的阻力）

ASM cell hypertrophy and hyperplasia potentially increase force generation even if the contractile properties remain normal. 细胞增生及肥大，增加收缩力，即使弹性正常

However, ASM is highly plastic, that is, it can change its contractile phenotype when exposed to inflammatory mediators, persistent contraction and altered length. Thus, increased ASM bulk, combined with increased contractility that is optimized for any given ASM length (i.e. airway diameter) will contribute to AHR.

然而，ASM 具有高度可塑性，也就是说，当暴露于炎症介质、持续收缩和长度改变时，它可以改变其收缩表型。 因此，增加的 ASM 体积，结合增加的针对任何给定 ASM 长度（即气道直径）优化的收缩性将有助于 AHR。

Increased tissue mass and altered composition of the airway wall, particularly of the extracellular matrix (ECM), may alter the airway wall mechanics and contribute to AHR and non-reversible airway narrowing. patients are stiffer than those from non-asthmatic patients. This would prevent deep inspirations from dilating airways, but paradoxically it could also resist airway narrowing.

气道壁组织质量的增加和气道壁成分的改变，特别是细胞外基质 (ECM) 的成分，可能会改变气道壁力学并导致 AHR 和不可逆的气道狭窄。 患者比非哮喘患者更僵硬。 这将防止深吸气扩张气道，但矛盾的是，它也可以阻止气道变窄。

In any event, an in vitro study of intact bronchial segments has shown that the increased thickness of the ASM layer is associated with increased maximal airway narrowing in asthma

无论如何，对完整支气管段的体外研究表明，ASM 层的厚度增加与哮喘中最大气道狭窄的增加有关

5. AIRWAY REMODELLING: THE COMPLEX BRANCHING SYSTEM

Airway segments do not act in isolation but are integrated into the moving, branching system of airways acting in parallel and in series.

Results suggest that both the large and peripheral airway compartments are relevant in severe asthma.

The role of the peripheral airways in AHR and fixed airway narrowing in severe asthma remains poorly understood.

• because the peripheral airways are the ‘silent zone’, contributing only about 10% of the total airway resistance. 
• Currently, they cannot be visualized by imaging and biopsy of the lung periphery is inherently confined to a tiny sample of the small airways and associated with significant risk (bleeding and pneumothorax).

Small airway function

measured by ventilation heterogeneity (synonymous with inhomogeneity), which is the variability of ‘specific ventilation’ (ventilation per unit lung volume). 每单位肺容积的通气量

Healthy lungs ventilate

• heterogeneously but in a highly spatially organized pattern along the gravitational gradient健康的肺通风有些不均匀，但沿重力梯度以高度空间组织的模式进行
• Specific ventilation is greatest in the dependent zones, unless there is airway closure present, which can be thought of as the extreme end of the distribution of ventilation within a lung. 通气量最大：dependent zone (肺内通气分布的最末端)

Asthma ventilation

• more heterogeneous compared with health
• with more widespread and patchy airway closure

Abnormalities of small airway function

• measured by ventilation heterogeneity using the single-breath nitrogen washout (SBNW) and multiple-breath nitrogen washout (MBNW) 
• associated with 
• asthma symptoms
• severe asthma exacerbations
• loss of control on withdrawal of treatment
• airway inflammation
• AHR

The relationship between small airway function and remodelling remains unknown. 

It has been proposed that peripheral airways influence symptoms, AHR and exacerbations due to airway inflammation and remodelling causing them to be unstable and prone to sudden closure.

The mechanism of this computational instability is that small airways are highly interconnected via parenchymal tissue 

Bronchoconstriction and closure in one airway affect its neighbours with the net result of small airways ‘self-organizing’ into zones of closure or severe hypoventilation.

When bronchoconstriction occurs, 

• some airways contract excessively
• induces more airway narrowing and closure in its neighbours
• creating a feed-forward loop
• leads to excessive and widespread narrowing and closure that occurs within zones or regions in the lungs that are easily detected by imaging

6. REMODELLING IN SEVERE ASTHMA

In severe asthma, airway walls are 

• thicker on HRCT
• have more fibroblasts
• larger mucous glands
• increased ASM
• greater epithelial fragility
• increased blood vessels in the lamina propria.
• ASM hyperplasia 
• ASM hypertrophy
• ECM is increased in the ASM 
• although this is in proportion to the increase in ASM. 
• Specific ECM proteins are also increased in asthma, although these may vary across the airway wall.

Although structural changes in postmortem lungs following fatal asthma attacks may not necessarily be generalizable to severe asthma, there are similar changes in postmortem and biopsy tissue of non-fatal but clinically severe asthma, relative to mild cases and non-asthmatic individuals. 不一定有结构上的改变

主要改变在 large airways

不在small airways： due to the small absolute size of the airways and variation in airway number and size. 

• However, the small airways are more susceptible to severe narrowing and closure due to the greater wall area relative to the airway lumen area.

保持气道口径的结构

The peripheral airways are tethered to the surrounding lung parenchyma which maintains airway calibre and prevents excessive narrowing and closure. 

严重哮喘的尸检发现

Postmortem, lung resection and transbronchial biopsy studies in severe asthma show neutrophilic, eosinophilic and lymphocytic inflammation and remodelling in the peripheral airways extending to the adventitia and lung, closely resembling that seen in the large airways. 

Remodelling of the ASM in the small airways also resembles ASM remodelling in the large airways.

Inflammation in the small airways could

break adjacent adventitial attachments

described in fatal asthma

reduce elastic recoil pressure

described in long-standing asthma and during asthma exacerbations.

为什们reduced lung density on computed tomography (CT) scans?

Reduced lung elastic recoil pressure

• increased small airway collapse and gas trapping during expiration and fixed airway narrowing, all of which are well described in severe asthma. 
• Recently, increased contractile elements have been documented in the lung parenchyma in asthma