Abstract
Because histopathological changes in the lungs of patients with systemic sclerosis (SSc) are consistent with alveolar and vessel cell damage, we presume that this interaction can be characterized by analyzing the expression of proteins regulating nitric oxide (NO) and plasminogen activator inhibitor-1 (PAI-1) synthesis. To validate the importance of alveolar-vascular interactions and to explore the quantitative relationship between these factors and other clinical data, we studied these markers in 23 cases of SSc nonspecific interstitial pneumonia (SSc-NSIP). We used immunohistochemistry and morphometry to evaluate the amount of cells in alveolar septa and vessels staining for NO synthase (NOS) and PAI-1, and the outcomes of our study were cellular and fibrotic NSIP, pulmonary function tests, and survival time until death. General linear model analysis demonstrated that staining for septal inducible NOS (iNOS) related significantly to staining of septal cells for interleukin (IL)-4 and to septal IL-13. In univariate analysis, higher levels of septal and vascular cells staining for iNOS were associated with a smaller percentage of septal and vascular cells expressing fibroblast growth factor and myofibroblast proliferation, respectively. Multivariate Cox model analysis demonstrated that, after controlling for SSc-NSIP histological patterns, just three variables were significantly associated with survival time: septal iNOS (P=0.04), septal IL-13 (P=0.03), and septal basic fibroblast growth factor (bFGF; P=0.02). Augmented NOS, IL-13, and bFGF in SSc-NSIP histological patterns suggest a possible functional role for iNOS in SSc. In addition, the extent of iNOS, PAI-1, and IL-4 staining in alveolar septa and vessels provides a possible independent diagnostic measure for the degree of pulmonary dysfunction and fibrosis with an impact on the survival of patients with SSc.
Highlights
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular abnormalities, fibrosis of the skin, musculoskeletal manifestations, and internal organ involvement [1]
We demonstrated higher expressions of inducible NOS (iNOS) in alveolar and vascular structures in patients with systemic sclerosis (SSc) when compared with the normal lung tissue group
Alveolar structures and vessels had a high expression of iNOS in epithelial, endothelial, myofibroblasts, and smooth muscle cells
Summary
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular abnormalities, fibrosis of the skin, musculoskeletal manifestations, and internal organ involvement [1]. There is great interest to identify which NSIP groups are likely to progress to a more fibrotic pattern that may result in shorter patient survival. Identification of these specific NSIP groups after surgical lung biopsy may allow for optimal treatment approaches. In this regard many have studied biological markers in alveolar as well as in vascular compartments to discover what might relate with the progression of fibrosis or treatment responses, or to tumor recurrence and shortened survival [8,9,10,11,12]. Several interleukins (IL4, IL-6, IL-8, and IL-13) and growth factors [transforming growth factor beta (TGF-b), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF-a), insulin-like growth factors (IGFs), basic fibroblast growth factor (bFGF), and interferon gamma (IFN-c)] released from
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