Abstract
BackgroundSeveral studies have implicated a role of inflammation in the pathogenesis of lung damage in idiopathic pulmonary fibrosis (IPF). Parenchymal lung damage leads to defects in mechanics and gas exchange and clinically manifests with exertional dyspnea. Investigations of inflammatory cells in IPF have shown that eosinophils, neutrophils and CD8+ TLs may be associated with worse prognosis. We wished to investigate by quantitative immunohistochemistry infiltrating macrophages, neutrophils and T lymphocytes (TLs) subpopulations (CD3+, CD4+ and CD8+) in lung tissue of patients with IPF and their correlation with lung function indices and grade of dyspnoea.MethodsSurgical biopsies of 12 patients with IPF were immunohistochemically stained with mouse monoclonal antibodies (anti-CD68 for macrophages, anti-elastase for neutrophils, and anti-CD3, anti-CD4, anti-CD8 for CD3+TLs, CD4+TLs, and CD8+TLs respectively). The number of positively stained cells was determined by observer-interactive computerized image analysis (SAMBA microscopic image processor). Cell numbers were expressed in percentage of immunopositive nuclear surface in relation to the total nuclear surface of infiltrative cells within the tissue (labeling Index). Correlations were performed between cell numbers and physiological indices [FEV1, FVC, TLC, DLCO, PaO2, PaCO2 and P(A-a)O2)] as well as dyspnoea scores assessed by the Medical Research Council (MRC) scale.ResultsElastase positive cells accounted for the 7.04% ± 1.1 of total cells, CD68+ cells for the 16.6% ± 2, CD3+ TLs for the 28.8% ± 7, CD4+ TLs for the 14.5 ± 4 and CD8+ TLs for the 13.8 ± 4. CD8+TLs correlated inversely with FVC % predicted (rs = -0.67, p = 0.01), TLC % predicted (rs = -0.68, p = 0.01), DLCO % predicted (rs = -0.61, p = 0.04), and PaO2 (rs = -0.60, p = 0.04). Positive correlations were found between CD8+TLs and P(A-a)O2 (rs = 0.65, p = 0.02) and CD8+TLs and MRC score (rs = 0.63, p = 0.02). Additionally, CD68+ cells presented negative correlations with both FVC % predicted (rs = -0.80, p = 0.002) and FEV1 % predicted (rs = -0.68, p = 0.01).ConclusionIn UIP/IPF tissue infiltrating mononuclear cells and especially CD8+ TLs are associated with the grade of dyspnoea and functional parameters of disease severity implicating that they might play a role in its pathogenesis.
Highlights
Several studies have implicated a role of inflammation in the pathogenesis of lung damage in idiopathic pulmonary fibrosis (IPF)
All patients claimed some degree of dyspnoea (MRC score > 0) and most patients had a restrictive lung function pattern characterized by a decrease in total lung capacity (TLC) and an increased in FEV1/FVC ratio ×100
This study shows that the type of the inflammatory infiltrate in lung tissue of patients with usual interstitial pneumonia (UIP)/IPF was predominantly mononuclear, and that among the different inflammatory cells, CD8+ T lymphocytes (TLs) correlated significantly with both functional [FVC, TLC, DLCO, PaO2, P(A-a)O2] and clinical indices of the disease severity and extent studied and macrophages (CD68+ cells) with some of the functional indices studied (FVC and FEV1)
Summary
Several studies have implicated a role of inflammation in the pathogenesis of lung damage in idiopathic pulmonary fibrosis (IPF). UIP/ IPF was regarded to develop in response to chronic inflammation of the lung parenchyma [4] This view was advanced from previous studies implicating a role of the inflammatory cells including neutrophils, macrophages, eosinophils and T lymphocytes (TLs), based on the observation of their accumulation in sites of disease activity [58] or on their presence in high numbers in bronchoalveolar lavage [9,10,11,12]. The current pathogenetic theory that holds in UIP/IPF, implicates that fibrosis per se might progress despite a paucity of interstitial inflammation [13] Even in this case, recent data still indicate the contention that the type of the inflammatory response may modulate tissue injury, fibrosis or both [3,4]. In UIP/IPF, the inflammatory response is considered to resemble closely the type-2 T lymphocytic pattern [16,17,18] and drives the process in a profibrogenic direction
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