Inflammation and changes to the lung tissue is not commonly associated with asthma because it is typically thought of as a disease affecting the airways. Contribution of lung tissue to asthma pathogenesis is not well recognized because evidence is limited and based on a small number of post-mortem and bronchoscopy studies (160, 208, 209, 247, 248). Inflammation and breakdown of lung tissue in asthma may occur as a result of inflammation extending from the outer or adventitial layer of the small airways to the surrounding alveolar walls. This is based on inflammation occurring predominantly in the adventitial layer in the small but not large asthmatic airways (160, 247, 248).
Inflammatory process occurring in the lung or alveolar tissue has also been demonstrated in living stable asthmatics (208). The predominant inflammatory
cells were eosinophils and macrophages and were greater in number in the alveolar tissue compared to airway tissue (208). Inflammation is also accentuated during the night in nocturnal asthmatics, suggesting circadian variation may contribute to lung tissue inflammation (208). Nocturnal decline in lung function is associated with eosinophils in the alveolar but not proximal airway tissue (208). Additionally, in nocturnal asthmatics a greater number of CD4+ lymphocytes were found in alveolar tissue during the night, compared to non-nocturnal asthmatics (209). Alveolar tissue but not airway CD4+ cells, which are cells that can drive eosinophil recruitment, also correlate with nocturnal worsening of lung function (209).
1.6.3.1. Lung tissue breakdown and proteolytic cascade
It has been proposed that bronchiolar inflammation results from recurrent asthma attacks, which in turn activates a pro-inflammatory proteolytic pathway that can cause tissue breakdown (16, 18, 197, 198, 249). This pathway is mediated by an autocrine epidermal growth factor (EGFR) signalling cascade, also initiated by inhalation of aeroallergens or noxious stimuli (249). Protective mucociliary responses occur in the epithelium via IL-17 and IL-18, which activates IL-8 to induce mucin production and promote neutrophil recruitment (198, 249). Mucin production can also be induced by proteases including neutrophil elastase and cathepsin G and by eosinophils, macrophages and mast cells via activation of the EGFR ligand-initiated signally cascade (249). These proteases together with activated MMPs are part of the proteolytic cascade, which could potentially cleave and disrupt terminal bronchiole-lung tissue attachments (249). Consequently lung tissue breakdown may lead to
mild emphysema (18, 198), similar to the terminal bronchiole-lung tissue uncoupling seen in smokers with emphysema (250). A pro-inflammatory proteolytic cascade can explain lung tissue breakdown in both these situations.
Indirect evidence of MMPs contributing to this proposed mechanism of lung tissue breakdown in asthma has been demonstrated in autopsy studies (191). Increased content of MMP-1, MMP-2 and MMP-9 was found in the outer area of the small airways (i.e. areas of the airway wall in close proximity to alveolar tissue) in those who died from asthma compared to non-asthmatics who died from other causes (191). Composition of ECM proteins in the outer airway wall was also altered in the asthmatic patients; fibronectin was increased and collagen III was reduced (191). Additionally, in the peri-bronchiolar lung tissue of the asthmatic patients MMP-9 and collagen I content was increased (191) (figures 1.7 and 1.8). The presence of proteolytic proteases (MMPs) and changes to the outer airway wall in fatal asthmatics could therefore alter the mechanical properties between the airways and lung tissue.
Figure 1.7
From Dolhnikoff et al (191).
The distal lung is a major site of extracellular matrix (ECM) remodelling in fatal asthma, with an imbalance of collagens I and III and increased fibronectin and matrix metalloproteinase (MMP) content. This diagram summarises the differences in ECM composition in the small airways between healthy controls and patients with fatal asthma. !: Significantly lower compared with that seen in healthy controls. ": Significantly higher compared with that seen in healthy controls.
Figure 1.8
From Dolhnikoff et al (191).
Fibronectin and matrix metalloproteinase-9 (MMP-9) content (in square micrometers per micrometer) in the small airways and peri-bronchiolar lung tissue in asthmatic patients and control subjects. IS: inner area of the small airways, OS: outer area of the small airways, PP: peri-bronchiolar parenchyma or lung tissue. The median is represented as horizontal bars. Fibronectin: *P < 0.02 compared with control subjects. MMP-9: *P < 0.05 compared with control subjects.
There is also contradictory evidence showing MMP-9 is reduced in both airway and lung tissue in asthma compared to healthy controls (188). Although within the asthma group, those with uncontrolled asthma showed increased MMP-9 content compared to the controlled asthmatics (188). Additionally, the amount of tissue-inhibitor of MMP-3 was increased in the asthmatics compared to healthy controls in both airway and lung tissue (188). Inflammation in asthma is now recognized as being more diverse, with eosinophilic and neutrophilic inflammation often co-existing. The type of inflammation present relates to various clinical features of asthma (62) and importantly, the lack of eosinophilia and response to corticosteroids does not rule out asthma. It is likely that more than one inflammatory cell and pathway are involved in the various asthma phenotypes and contribute to inflammation and alteration to the inflammatory profile over time (222). Inflammation of the lung tissue should not be ignored because it is likely to play a role in airway- lung tissue uncoupling and therefore alter the mechanical function and inter- dependence (160, 191, 247, 248). The functional consequences of airway and lung tissue changes in asthma will be discussed in the next section.