The results of this study demonstrate there is a significant increase in the density of chymase-immunoreactive mast cells in the lung tissue of patients with IPF, and suggest that mast cell density is related inversely to disease progression. These findings suggest that mast cells may influence the pathogenesis of IPF by attenuating the progression of fibrosis.
Previous studies have reported an abundance of mast cells in IPF lungs.14,15,19
However, these studies were performed prior to the reclassification of idiopathic interstitial pneumonias and did not contain diseased controls.2
Using the new classification scheme to identify patients with IPF, the present study confirmed that the density of mast cells is increased in IPF lungs. This study also examined whether mast cell hyperplasia is unique to IPF or a general feature of fibrotic lung diseases such as chronic HP and SSc-related ILD. Remarkably, mast cell density was highest in IPF lungs and elevated in HP patients compared to controls. Furthermore, the mast cell density in fibrotic lungs from SSc patients was similar to normal controls, suggesting that mast cell recruitment to fibrotic lungs may be disease-specific and not simply a general feature of lung fibrosis.
Previous studies have evaluated the prognostic value of histopathological features of IPF.28–34
For example, the number of fibroblastic foci predicts a worse prognosis.29,31–33
In addition, the presence of eosinophils in bronchoalveolar fluid of patients with lung fibrosis predicts disease progression and worse survival.35,36
The data in this manuscript are unique, because they suggest that lung mast cell density may predict disease progression in IPF patients, with higher lung mast cell density being associated with slower disease progression. The use of mast cell density as a histopathological predictor of survival will require further study.
The role played by mast cells in the pathogenesis of fibrotic lung disease remains undefined. The majority of reports suggest mast cells promote lung fibrosis.14,19,20
In this IPF cohort, a subgroup classified as having a high mast cell density exhibited a slower rate in decline of FVC compared to a subgroup with low mast cell density. Decline in FVC over time is an accepted marker of disease progression in IPF that correlates with worse prognosis.37–39
Therefore, these data suggest that presence of mast cells in the lungs of IPF patients may protect against, rather than contribute to, disease progression.
The underlying mechanism for the increased mast cell numbers in lungs of a subset of IPF patients remains undefined. T helper type 2 (Th2) cytokines have been reported to play a role both in allergic inflammation40
and the pathogenesis of IPF.41
Because mast cells and eosinophils are prominent in both pathological processes, and because eosinophils and mast cells are markers of Th2 immune responses, one potential explanation is that mediators of Th2 immune response recruit both mast cells and eosinophils to IPF lung.36
To examine this possibility, the density of mast cells was correlated to eosinophils in the lung tissue of IPF patients. Importantly, the mast cell density in IPF lung did not correlate with eosinophil density in IPF lungs, suggesting that mast cells and eosinophils in the lung tissue of IPF are recruited to IPF lungs by different biological processes.
Controversy regarding the role of inflammation in the pathogenesis of IPF persists,42
with the prevailing hypothesis being that inflammation does not play a major role in the pathogenesis of IPF.43–45
Our data are notable because they correlate the presence of mast cells, a specific type of inflammatory cell, with slower loss of lung function in IPF patients. This suggests that the relative role of inflammation in the progression of IPF should be considered more broadly, including the possibility that inflammation attenuates, rather than augments, disease progression.
This study has several limitations. First, because lung tissues were obtained randomly from the patients’ lungs, the lung tissue sampled may not be representative of pathological changes present in regions of lung that were not sampled. This is probably of limited importance because all biopsies included sub-pleural tissue, the region of lung involved most commonly in IPF. Secondly, as the study was performed retrospectively, a selection bias may have occurred because the analysis of physiological parameters was limited to a subgroup of patients with available longitudinal data. Thirdly, because lung tissues were obtained only once, the stage of disease could have biased the mast cell density. Fourthly, gender could have influenced measures of disease progression, as there were proportionately more males in the low mast cell group. To overcome these limitations, a prospectively designed study including larger number of patients is necessary to confirm the protective role of mast cells against the progression of IPF.
In conclusion, mast cell density is higher in IPF lungs compared to other fibrotic ILDs and normal lung. A higher mast cell density correlates with slower disease progression in IPF patients. These results suggest that mast cells may play an important role in attenuating the fibrotic process in IPF patients.