Squamous Cell Carcinoma Antigen (SCCA)-2 Is Overexpressed in End-Stage Idiopathic Pulmonary Fibrosis and Correlates with Epithelial Proliferation
F Lunardi, M Loy, E Balestro, G Marulli, M Valente, F Rea, F Calabrese. University of Padua, Padua, Italy
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology. A high incidence of lung cancer in patients with IPF is the main reason for the poor prognosis of the disease. Abnormal re-epithelization with aberrant proliferation of metaplastic cells often observed in highly remodeled fibrotic areas are believed to be a part of the precancerous process leading to lung cancer. Squamous cell carcinoma antigens (SCCA)-1/2 (also known as SERPIN B3/B4), are members of the serpin superfamily and fundamental for the control of proteolysis through an inhibitory function of different proteases. Recently several studies have documented an important role of SCCA-1/2 in the modulation of fibrosis, including lung fibrosis. The aim of this study was to confirm the role of SCCA in lung fibrosis and investigate its influence on epithelial proliferation. The most prevalent isoform, SCCA-1 or SCCA-2, was also studied.
Design: Native lungs of 47 patients consecutively transplanted for IPF (Group A: 33 males and 14 females; mean age±standard deviation: 55±7 years; DLCO, mean±SD: 23±10% of predicted values, three of them with histological foci of neoplastic transformation) were studied. Ten native lungs of non-IPF subjects (Group B) were used as a control group. In consecutive serial sections from all cases immunohistochemistry for SCCA-1/2, transforming growth factor (TGF)β and Ki-67 was performed and the quantification restricted to strongly stained metaplastic epithelial cells distinguishing cuboidal, bronchiolar and squamous cells. Values were expressed as percentages of positive cells and Ki-67+ cells represented the proliferative index (PI). Quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used to characterize the most prevalent SCCA isoform in all cases.
Results: SCCA was overexpressed in Group A (median values, range: 32% of cuboidal, 9-65%; 36% of bronchiolar, 14-61%; and 88% of squamous cells, 24-96%), and only sporadically detected in Group B (median, range: 2%, 0-6%). SCCA expression was directly correlated to both PI (p<0.05) and TGFβ (p<0.0001). Although SCCA-1 was present in all patients, SCCA-2 was overexpressed in IPF patients.
Conclusions: These results confirm the strict relation between SCCA-1/2 and the pro-fibrogenetic cytokine TGFβ. The isoform SCCA-2 plays a key role in aberrant regeneration occurring in IPF.
Tuesday, March 23, 2010 2:00 PM
Platform Session: Section F, Tuesday Afternoon