Inflammatory Cell Phenotyping of the Pulmonary Interstitium in Idiopathic Interstitial Pneumonia

Background: Several studies have implicated the role of inflammation in the pathogenesis of lung damage in idiopathic interstitial pneumonias (IIPs). Investigations of inflammatory cells in IIP have show that eosinophils, neutrophils and T cells may be associated with a poorer prognosis. Objectives: The aim of our study was to map, by quantitative analysis, the number of inflammatory cells in the lung tissue of patients with non-specific interstitial pneumonia/non-specific interstitial pneumonia (NSIP/NSIP), acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD) and idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP) and to correlate them with lung function tests and survival. Methods: After immunohistochemical staining, we quantified the content of inflammatory cells [macrophages, neutrophils (elastase+), plasma cells, and CD3, CD4 and CD8 T lymphocytes (TLs)] in 20 NSIP, 20 DAD and 20 UIP surgical lung biopsies. Results: The total density of inflammatory cells was significantly increased in DAD and NSIP when compared to UIP (p = 0.04). TLs were increased in DAD and NSIP when compared to UlP lungs (p < 0.05). The density of inflammatory cells in UIP showed significant differences in normal, intervening and dense fibrosis areas (p < 0.05). The most numerous cells infiltrating the mural fibrosis and honeycombing areas were plasma cells, neutrophils (elastase+), CD20+, CD3+, CD4+ and CD8+ (p < 0.05). In UIP, CD3+ TLs were directly correlated with forced expiratory volume in 1 s/forced vital capacity ratio × 100 (p = 0.05). CD68+ cells presented a significant positive correlation with the forced expiratory volume in 1 s (p = 0.04); neutrophil (elastase+) cells significantly correlated with residual volume (p = 0.02), residual volume/total lung capacity (p = 0.04) and carbon monoxide transfer factor (p = 0.03). The most important predictor of survival in UIP was CD3+ TLs (p = 0.05). Conclusion: The total density of inflammatory cells and lymphocytes presents a different distribution within the pulmonary parenchyma in AIP/DAD, NSIP/NSIP and IPF/UIP evolutionary adapted responses to injury. There is a localized distribution of inflammation in the normal, intervening and dense fibrosis areas of UIP for CD3+, associated with a lethal deterioration of the pulmonary function and poor survival. Our findings provide further evidence of the importance of inflammation in the pathophysiology of IIPs.

[1]  M. Mishima,et al.  Cell Profiles of Bronchoalveolar Lavage Fluid as Prognosticators of Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia among Japanese Patients , 2005, Respiration.

[2]  H. Mukae,et al.  Increased Levels of Interleukin-18 in Bronchoalveolar Lavage Fluid of Patients with Idiopathic Nonspecific Interstitial Pneumonia , 2005, Respiration.

[3]  N. Siafakas,et al.  Induced Sputum versus Bronchoalveolar Lavage Fluid in the Evaluation of Patients with Idiopathic Pulmonary Fibrosis , 2005, Respiration.

[4]  E. White,et al.  Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis , 2003, The Journal of pathology.

[5]  J. Müller-Quernheim,et al.  Systemic Immune Cell Activation in a Subgroup of Patients with Idiopathic Pulmonary Fibrosis , 2003, Respiration.

[6]  Carl Nathan,et al.  Points of control in inflammation , 2002, Nature.

[7]  A. Katzenstein,et al.  Usual Interstitial Pneumonia: Histologic Study of Biopsy and Explant Specimens , 2002, The American journal of surgical pathology.

[8]  Paul J. Friedman,et al.  American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors , 2002, American journal of respiratory and critical care medicine.

[9]  R. Strawderman,et al.  Histopathologic variability in usual and nonspecific interstitial pneumonias. , 2001, American journal of respiratory and critical care medicine.

[10]  S. Sleijfer.  Bleomycin-induced pneumonitis. , 2001, Chest.

[11]  A. Pardo,et al.  Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy , 2001, Annals of Internal Medicine.

[12]  J. Fujita,et al.  Lymphocyte Subsets in Lung Tissues of Non-specific Interstitial Pneumonia and Pulmonary Fibrosis Associated with Collagen Vascular Disorders: Correlation with CD4/CD8 Ratio in Bronchoalveolar Lavage , 2000, Lung.

[13]  J. Myers,et al.  Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. , 1998, American journal of respiratory and critical care medicine.

[14]  F. Martinez,et al.  Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. , 1997, AJR. American journal of roentgenology.

[15]  T. Mosmann,et al.  The expanding universe of T-cell subsets: Th1, Th2 and more. , 1996, Immunology today.

[16]  Hui Hu,et al.  Hapten‐immune pulmonary interstitial fibrosis (HIPIF) in mice requires both CD4+ and CD8+ T lymphocytes , 1993, Journal of leukocyte biology.

[17]  J E Cotes,et al.  Lung volumes and forced ventilatory flows , 1993, European Respiratory Journal.

[18]  J. Roca,et al.  Standardization of the measurement of transfer factor (diffusing capacity). Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. , 1993, The European respiratory journal. Supplement.

[19]  J E Cotes,et al.  Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. , 1993, The European respiratory journal. Supplement.

[20]  R. Colvin,et al.  Usual interstitial pneumonitis is a T-cell alveolitis. , 1986, Clinical immunology and immunopathology.

[21]  B. Rabin,et al.  Lymphocyte phenotypes in bronchoalveolar lavage and lung tissue in sarcoidosis and idiopathic pulmonary fibrosis. , 1986, The American review of respiratory disease.

[22]  R. D. du Bois,et al.  Immunohistological analysis of lung tissue from patients with cryptogenic fibrosing alveolitis suggesting local expression of immune hypersensitivity. , 1985, Thorax.

[23]  P. Haslam.  Evaluation of alveolitis by studies of lung biopsies , 2007, Lung.

[24]  Konrad Sandau,et al.  Unbiased Stereology. Three‐Dimensional Measurement in Microscopy. , 1999 .

[25]  M. Schwarz,et al.  A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. , 1986, The American review of respiratory disease.