‘To measure is to know’ (Lord Kelvin)

Asthma is an important and still sometimes fatal airways disease that relies on an accurate clinical diagnosis. A substantial body of research studies have contributed to a modern paradigm, indicating that both airway inflammatory and structural changes are associated with abnormal airway physiology. Both eosinophilic and neutrophilic inflammations have been described, and studies of induced sputum have been prominent and valuable. Such information has been used to predict response to therapies, including ‘new era’ anti-cytokine therapies.1

Information on structural changes in asthma is arguably harder to obtain, and there is less data, but the available studies commonly describe smooth muscle remodelling as an important component of structural change or ‘airway remodelling’ in the lungs of asthmatics.

Important insights have come from a series of painstaking studies from Perth, Western Australia, using post-mortem lung obtained from asthmatics.2, 3 This approach, albeit with inherent limitations, can combine descriptive but powerful information on both inflammatory and structural differences in asthmatics. In the latest such study, John Elliot, working with international colleagues, found that there were distinct distributions of airway smooth muscle remodelling seen in asthma and that pathology limited to small airways was uncommon.3 Airway smooth muscle thickening was associated with eosinophilia but not neutrophilia, and there were no significant differences in neutrophil density in the large airways of the 68 asthmatics compared with 37 controls studied, a considerable body of work.3 This observation underscores the concept that neutrophilic inflammation in asthma may be very hard to determine. It is also likely that in vivo both cell counts and cellular activity will be important in pathophysiology. Furthermore, although there is well-justified interest in the pathogenic roles of the neutrophil, its role in protective innate immunity is undisputed. As with other cell-focused hypotheses, we thus have to wait for specific anti-neutrophil interventions until the balance between defence and pathogenic roles of neutrophils in asthmatic airways can be decided.

Decades of induced sputum studies indicate that there are large percentages of neutrophils recovered from the airways of asthmatics. It is interesting that estimates of repeatability of sampling have wide limits of agreement, of the same magnitude as the mean levels of neutrophils observed.4 The present paper from Elliot et al. reframes an interesting question about the precise origin of the cells contained in induced sputum samples. It has been suggested, logically, that induced sputum reflects the cells present in the large airways,5 and further that elevated neutrophils are associated with more severe asthma.6 This creates a paradox with the findings of the present study of post-mortem lung, which indicated that there were no differences in neutrophil density in the large airways between asthma and controls.3 The current study also points out that airway smooth muscle remodelling, a central tenet of the modern asthma paradigm, was not present in 37% of cases, commonly but not exclusively, in the mild to moderate asthmatics.

The current asthma literature is replete with analyses of sputum samples representing the bronchial lumen. Yet the major disease processes occur in the bronchial wall, commendably investigated by Elliot et al. Indeed, the airway lumen, whether in large or small airways, in part serves as a route of elimination of the bronchial wall cells. Hence, it is unsurprising that patients exhibit sputum neutrophilia without increased neutrophil counts in the tissue.7 Discordant bronchial wall versus lumen granulocyte numbers can further be expected to occur depending on the phase of the inflammatory process.8 For example, at resolution of airway inflammation, increasing numbers of eosinophils and neutrophils in the bronchial lumen have been recorded along with decreased cellularity of the bronchial wall.8 Such observations constitute evidence that transepithelial exit is a clinically important mode of elimination of bronchial wall leucocytes. With eosinophils, in particular, significant elimination of bronchial wall cells occurs by migration across the epithelial lining, whether intact or deranged; this is in contrast with the current lack of compelling in vivo evidence for a role of apoptosis and phagocytosis of these cells.8

It is important that Elliot et al. have focused on granulocytes of the diseased bronchial tissue proper.3 We need more studies of this kind to improve our understanding of the role of granulocytes in asthma. The findings by Elliot et al. are an important context for emergent findings, where roles of eosinophils in asthma pathogenesis are being supported by the effects of novel drugs. A further aspect, which concerns both bronchial lumen and wall cells, concerns the mode of activation of eosinophils in asthma. It has emerged that these cells, rather than undergoing apoptosis, can exhibit a rapid and dramatic demise; they undergo primary lysis, thus spreading nuclear and cytosolic material including specific protein-rich granules. The free eosinophil granules, in turn, release their toxic cationic molecules in the diseased tissue.9 The particular process of cytolysis that uniquely affects eosinophils has only recently been highlighted, and little is known in detail about its regulation and its pharmacology. However, clinical asthma has associated better with the free toxic protein-releasing granules in the bronchial tissue than with numbers of eosinophils in the wall (or lumen). Lytic eosinophils may in fact be of key strategic importance in damaged tissue but would not be recorded in counts of intact eosinophils. Future studies on occurrence of eosinophil lysis and free eosinophil granule in bronchial walls are warranted to shed light on the potential roles of eosinophils in large and small airways even when counts of intact eosinophils are low.

An increasing range of therapeutic approaches are available for asthma. These include strategies targeting airway smooth muscle through bronchial thermoplasty and anti-cytokine therapy, which are potentially personalized to individual patient inflammation. The valuable study of Elliot et al.,3 and others working in the field, reiterates the need for integrated studies of inflammatory and structural changes in asthma and response to therapy. In particular, more information on the variability of changes within and between asthma cases may be useful. Such work may help inform new therapeutic opportunities in asthma for ‘if you can not measure it, you can not improve it’ (Lord Kelvin).10