Characterisation of the proximal airway squamous metaplasia induced by chronic tobacco smoke exposure in spontaneously hypertensive rats

Sarah J Bolton,Victor Oreffo,Martyn Foster,Kent E Pinkerton,Kate Pinnion

doi:10.1186/1465-9921-10-118

Abstract

BackgroundContinuous exposure to tobacco smoke (TS) is a key cause of chronic obstructive pulmonary disease (COPD), a complex multifactorial disease that is difficult to model in rodents. The spontaneously hypertensive (SH) rat exhibits several COPD-associated co-morbidities such as hypertension and increased coagulation. We have investigated whether SH rats are a more appropriate animal paradigm of COPD.MethodsSH rats were exposed to TS for 6 hours/day, 3 days/week for 14 weeks, and the lung tissues examined by immunohistochemistry.ResultsTS induced a CK13-positive squamous metaplasia in proximal airways, which also stained for Ki67 and p63. We hypothesise that this lesion arises by basal cell proliferation, which differentiates to a squamous cell phenotype. Differences in staining profiles for the functional markers CC10 and surfactant D, but not phospho-p38, indicated loss of ability to function appropriately as secretory cells. Within the parenchyma, there were also differences in the staining profiles for CC10 and surfactant D, indicating a possible attempt to compensate for losses in proximal airways. In human COPD sections, areas of CK13-positive squamous metaplasia showed sporadic p63 staining, suggesting that unlike the rat, this is not a basal cell-driven lesion.ConclusionThis study demonstrates that although proximal airway metaplasia in rat and human are both CK13+ and therefore squamous, they potentially arise by different mechanisms.

Highlights

Continuous exposure to tobacco smoke (TS) is a key cause of chronic obstructive pulmonary disease (COPD), a complex multifactorial disease that is difficult to model in rodents
Our results indicate that the common pathology may arise via a different mechanism, and this may just be a reflection of inherent differences between rat and human, there is still considerable value in the utility of this rat stain for respiratory research
Our studies are in accordance with these results as we have demonstrated a loss of Clara Cell 10 kDa Protein (CC10) but an increase in p63+ basal cells

Summary

Introduction

Continuous exposure to tobacco smoke (TS) is a key cause of chronic obstructive pulmonary disease (COPD), a complex multifactorial disease that is difficult to model in rodents. Chronic obstructive pulmonary disease (COPD) is characterised pathologically by loss of lung elasticity, airspace enlargement, small airway remodelling and inflammation [1]. Repeated cycles of damage and repair to this mucosa in response to chronic TS exposure can result in bronchial epithelial squamous metaplasia, a histopathological feature of COPD, in moderate to severe disease (page number not for citation purposes). The epithelium is repopulated via resident basal cell proliferation, which differentiate to form a new mature epithelial barrier [5] Repeated insults such as continued smoking, or a delay in the differentiation and maturation of the epithelium can result in squamous metaplasia that becomes irreversible. The presence of squamous metaplasia has important pathological consequences

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