[The mechanism of lung tissue remodeling in the progression of idiopathic pulmonary fibrosis].

The aim of the investigation was to study the specific features of morphological manifestations and the molecular bases of lung tissue remodeling in progressive idiopathic pulmonary fibrosis (IPF). The investigation used open and transbronchial biopsy specimens from 110 patients with IPE/idiopathic pneumonia syndrome in 1997 to 2008. Immunohistochemical analysis was carried out on serial paraffin-embedded lung tissue slices from 20 patients with IPF and 20 control patients. Immunohistochemical staining for the detection of antigens in the paraffin-embedded slices was made using the antibodies to MMP-1, MMP-2, MMP-7, TIMP-4, Apo-CAS, PCNA, PDGF, EGFR, CD34, and SMA. Nonparametric statistical methods were employed. Our findings have indicated that in early-stage IPF, there are proliferating myofibroblasts in the myofibroblastic foci, mainly in the bronchioloalveolar transitional zone (BATZ), which express PCNA and PDGF. Both in early- and late-stage IPF, there were signs of increased readiness of the alveolar and bronchiolar epithelium of BATZ for apoptosis, as judged from Apo-CAS expression. At the same time no Apo-CAS expression was recorded in the myofibroblasts. In the early stage of the disease, the expression of MMP-1, MMP-2, MMP-7, and TIMP-4 in the epitheliocytes, macrophages, fibroblasts, and myofibroblasts was higher than that in the late stage of IPF. At the same time, late-stage IPF was characterized by the higher expression in all lung tissue cells than was early-stage IPF. There was also a significant increase in vessel density in both early and late stages of IPF as compared with intact lung tissue particularly in the BATZ in the control group. Thus, lung tissue remodeling in the progression of IPF from the early to late stage of the disease comprises interrelated processes that are largely localized in the BATZ, such as immune inflammation with pathological reparation, neoangiogenesis, apoptosis, and proliferation of epitheliocytes and myofibroblasts, which lead to the development of interstitial fibrosis and adenomatosis of the lung.

[Molecular bases for the development of variants of idiopathic fibrosing alveolitis].

The purpose of the study was to examine the specific features of morphological manifestations and molecular mechanisms of controlling the processes of proliferation, apoptosis, cell differentiation, neoangiogenesis, and fibrosis, which result in lung tissue rearrangement in different types of idiopathic fibrosing alveolitis (IFA). Open and transbronchial biopsy specimens obtained from 103 patients with IFA and intact lung tissue biopsy specimens taken from those clinically diagnosed as having sarcoidosis as a control group were examined. The serial paraffin sections immunohistochemically revealed the following antigens: cytokeratins 5, 6, 7, 8, 19 (Uni-Heidelberg, DAKO), MMP 1, MMP 2, MMP 7, and TIMP 4, Apo-protein (Novocastra), Ki67, PCNA, PDGF, EGFR, CD34, SMA (smooth muscle actin), FGFb (LabVision). Biotin-conjugated antibodies to murine and rabbit immunoglobulins (Dako LSAB + KIT, PEROXIDASE) were used as secondary antibodies. The nuclei were stained with hematoxylin. Positive and negative control tests were carried out. The results of immunohistochemical tests were estimated in percentage of cells showing positive reactions (Ki67, PCNA), as well as those of a semiquantitative analysis in scores and statistical analyses (Mann-Whitney U-test, Fisher's test, and Spearman's rank correlation coefficient) were employed. OIP was ascertained to differ from other IFA in higher values of the cytokines under study, as well as in the predominant rearrangement of the lung interstice and dysregeratory epithelial changes at the site of respiratory bronchiolar transformation. At the same time there was an intensive proliferation of the epithelium and stromal cells (high expression of PCNA, PDGF by hyperplastic alveolocytes, alveolar macrophages, fibroblasts and myofibroblasts), and neogenesis (the high density of newly formed vessels with endothelial expression of CD34). Elevated alveolocytic apoptosis (from Apo-protein expression) was also observed. Cell proliferation and neoangiogenesis was attained by high MMPs expression. The practical value of the study is that the expression of the study markers may serve as a criterion for differential diagnosis and determination of prognosis in different types of IFA.