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


METHODS
SH rats were exposed to TS for 6 hours/day, 3 days/week for 14 weeks, and the lung tissues examined by immunohistochemistry.


RESULTS
TS 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.


CONCLUSIONS
This study demonstrates that although proximal airway metaplasia in rat and human are both CK13+ and therefore squamous, they potentially arise by different mechanisms.
Bolton
Sarah J
SJ
Safety Assessment UK, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK. sarahj.bolton@astrazeneca.com
Pinnion
Kate
K
Oreffo
Victor
V
Foster
Martyn
M
Pinkerton
Kent E
KE
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D053535:Keratin-13 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia; D010641:Phenotype; D010766:Phosphorylation; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012907:Smoking / Q000009:adverse effects*; D013045:Species Specificity; D013997:Time Factors; D014598:Uteroglobin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C507426:KRT13 protein, human; D053535:Keratin-13; D019394:Ki-67 Antigen; C507428:Krt13 protein, rat; D037663:Pulmonary Surfactant-Associated Protein D; C556389:SCGB1A1 protein, human; C556391:Scgb1a1 protein, rat; D014598:Uteroglobin; D048051:p38 Mitogen-Activated Protein Kinases