Association Between Genetic Variations In Surfactant Protein D and Emphysema,Interstitial Pneumonia,and Lung Cancer in a Japanese Population

Abstract

Surfactant protein D (SFTPD) is a lung-specific anti-inflammatory factor that antagonizes inflammation by inhibiting oxidative stress and stimulating innate immunity. Variations in SFTPA2 and SFTPB, genes for other surfactant proteins, have been associated with lung cancer. We therefore investigated associations between SFTPD variations and lung cancer as well as emphysema and interstitial pneumonia, which are characterized by chronic inflammation from which lung cancer often arises. DNA from 1342 autopsy samples, including those from 140 subjects with lung cancer, was investigated. The single nucleotide polymorphism (SNP) rs721917, which results in methionine being exchanged for threonine at amino acid 11 (the Met11Thr variation), tended to be associated with emphysema and was associated with interstitial pneumonia and lung cancer. A haplotype analysis revealed that the haplotypes associated with emphysema and lung cancer differed from that associated with interstitial pneumonia, suggesting a differential role for SFTPD in the development of these diseases. A mediating analysis did not reveal a mediating effect exerted by emphysema or interstitial pneumonia on lung cancer. Our results suggested that SFTPD plays a role in the development of lung cancer and that the role for lung cancer may differ from that for interstitial pneumonia.     

Pneumomediastinum and subcutaneous emphysema secondary to amyopathic dermatomyositis with cryptogenic organizing pneumonia in invasive breast cancer: a case report and review of literature

Amyopathic dermatomyositis (ADM) is recognized as a variant phenotype of dermatomyositis and characterized by typical skin manifestations without evidence of muscular inflammation. While interstitial lung disease (ILD) is occasionally found as one of the lung manifestations in ADM patients, the development of a pneumomediastinum and/or subcutaneous emphysema in this disease entity is one of the extremely rare pulmonary complications. These latter complicated pulmonary manifestations have been usually reported in idiopathic ADM with ILD without any other associated medical conditions. We report a case presented with the spontaneous pneumomediastinum and subcutaneous emphysema in both ADM and cryptogenic organizing pneumonia during adjuvant chemotherapy based on cyclophosphamide for breast cancer.     

99mTc-DTPA aerosol deposition and clearance in COPD, interstitial disease, and smokers

The application of 99mTc-DTPA radioaerosols to a variety of clinical disorders is described. With the development of simple equipment that can deliver very small droplets, this approach has become increasingly popular for measurements of the distribution of ventilation in patients with obstructive lung disease and suspected pulmonary embolism. In addition, by determining the rate at which the radionuclide is cleared from the lung, information has been obtained concerning the permeability of the pulmonary epithelium to extracellular indicators. Accelerated clearance rates have been found in patients with a variety of chronic interstitial lung diseases indicating that epithelial permeability is increased. Accelerated clearance rates have also been found with acute inflammation of the lung such as the adult respiratory distress syndrome and pneumocystis pneumonia. Furthermore, rapidly reversible increases in 99mTc-DTPA clearance occur in smokers and may be related to the inflammatory changes that contribute to the development of emphysema.     

Smoking‐related idiopathic interstitial pneumonia: A review

For many years, cigarette smoking has been considered as the leading cause of chronic obstructive pulmonary disease and lung cancer. Recently, however, it has also been associated with the development of diffuse interstitial lung diseases. In the latest classification of the major idiopathic interstitial pneumonias (IIP), the term smoking‐related IIP has been introduced, including two entities, namely desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis‐interstitial lung disease (RB‐ILD). Other entities in which smoking has a definite or suggested role include pulmonary Langerhan's cell histiocytosis, smoking‐related interstitial fibrosis, combined pulmonary fibrosis and emphysema syndrome and idiopathic pulmonary fibrosis. In this review, we will focus on the mechanisms of smoking‐related lung damage and on the clinical aspects of these disorders with the exception of idiopathic pulmonary fibrosis, which will be reviewed elsewhere in this review series.     

Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: report of eight cases and review of the literature

INTRODUCTION: Smoking can cause a variety of pulmonary interstitial diseases. Pulmonary fibrosis has traditionally been considered a non-smoking-related disease. Recently, however, evidence of smoking-induced fibrosis has emerged. SUBJECTS AND METHODS: A group of eight patients from the pulmonary clinic in Rabin Medical Center with a combine presentation of fibrosis and emphysema was identified retrospectively. All patients underwent chest computed tomography and pulmonary function tests. One patient underwent lung-heart transplantation and a complete review of his lung pathology was obtained. Transbronchial biopsy was performed in 3 additional patients and echocardiography was performed to evaluate the pulmonary vasculature. RESULTS: Upper-lobe emphysema with bulluos changes was found in all patients. In addition, a basal interstitial process was recognized, ranging from ground glass opacities to severe pulmonary fibrosis, with honeycombing. The radiological findings matched the pathological results of combined emphysema and usual interstitial pneumonia. Pulmonary function tests were also in accord, showing severe hypoxemia with mild obstruction, normal-to-mildly reduced lung volumes and a severe decrease in diffusion capacity. Most of the patients had moderate-to-severe pulmonary hypertension as well as diffuse coronary artery disease. CONCLUSION: Our findings are in line with emerging evidence that the spectrum of interstitial damage caused by smoke includes not only Langerhans cell hystiocytosis, respiratory bronchiolitis or desquamative interstitial pneumonia but also advanced usual interstitial pneumonitis as well. We believe that in some patients smoking plays a destructive role by a variety of mechanisms and can cause emphysema, lung fibrosis as well as pulmonary vasculopathy and hypertension. Future studies are needed to define the genetics and pathophysiology of this uncommonly reported clinical syndrome.     

Osteopontin levels are elevated in patients with eosinophilic pneumonia

Background and objective: Osteopontin is a key cytokine involved in pro‐inflammatory T helper type 1 (Th1)‐associated immune responses, which has recently been implicated in allergic diseases. We investigated the pathogenic role of osteopontin in eosinophilic pneumonia. Methods: The concentrations of osteopontin and Th1‐ or Th2‐associated cytokines were measured in BAL fluid (BALF) from 41 patients with eosinophilic pneumonia, including those with acute (AEP, n = 12), chronic (CEP, n = 16), or drug‐induced eosinophilic pneumonia (DEP, n = 13). The results were compared with those from patients with other interstitial lung diseases. Immunocytochemistry and double immunofluorescence labelling were performed to determine the cellular source of osteopontin. Results: Osteopontin was significantly elevated in BALF from patients with eosinophilic pneumonia as compared with BALF from patients with drug‐induced interstitial pneumonia, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, or sarcoidosis, and also compared with BALF from healthy volunteers. Osteopontin concentrations elevated at the time of exacerbation decreased during clinical improvement, either spontaneously or as a result of corticosteroid therapy. Elevated concentrations of CXCL10, CCL17 and IL‐10 were also detected in BALF from patients with eosinophilic pneumonia. Osteopontin concentrations in BALF of AEP patients were correlated with IL‐5, as well as IL‐10, CCL11, CCL17 and CXCL10 concentrations. In AEP and DEP patients, serum osteopontin concentrations were also elevated. Double immunofluorescence labelling showed that in patients with eosinophilic pneumonia, osteopontin was expressed in lung eosinophils. Conclusions: Osteopontin is likely to contribute to the development of inflammation in patients with eosinophilic pneumonia.     

Pulmonary interstitial emphysema is a risk factor for poor prognosis and a cause of air leaks

BackgroundPulmonary interstitial emphysema is a rare, abnormal condition in which air pressure from the alveolar airspace tears the adjacent interstitial tissues of the lung and causes the formation of cystic spaces. Pulmonary interstitial emphysema is a known indication for mechanical ventilation in premature infants with neonatal respiratory distress syndrome, and it can be observed in various types of interstitial lung disease. Nevertheless, its pathogenesis and clinical impact remain unknown.MethodsWe reviewed data from 433 cases of interstitial lung disease from an external consultation archive. Multidisciplinary diagnosis along with clinical and follow-up data, including events of air leaks such as pneumothorax and mediastinal emphysema, were obtained and compared to those of 150 control cases of interstitial lung disease without pulmonary interstitial emphysema.ResultsWe found 22 (5.1%) cases of interstitial lung disease with pulmonary interstitial emphysema. The diagnoses included idiopathic pulmonary fibrosis (5/22 [22.7%]), pleuroparenchymal fibroelastosis (4/22 [18.2%]), chronic hypersensitivity pneumonia (4/22 [18.2%]), and others (9/22 [40.9%]). Cases involving pulmonary interstitial emphysema demonstrated a significantly higher frequency of air leaks than did those without pulmonary interstitial emphysema (12/22 [54.5%] versus 23/150 [15.3%]; P < 0.001; odds ratio, 6.63) and were associated with worse prognosis (P = 0.009 [log-rank]) and a lower median percent forced vital capacity (73.2% versus 84.0%; P < 0.001).ConclusionsWe found that pulmonary interstitial emphysema is an independent factor for poor prognosis, which also shows a trend to cause air leaks, including pneumothorax and mediastinal emphysema.     

The relationship between ventilatory lung motion and pulmonary perfusion shown by ventilatory lung motion imaging

Using ventilatory lung motion imaging, which was obtained from two perfusion lung scintigrams with 99mTc-macroaggregated albumin taken in maximal inspiration and maximal expiration, the lung motion [E-I)/I) of the each unilateral lung was studied in various cardiopulmonary diseases. The sum of (E-I)/I(+) of the unilateral lung showed a decrease in the diseased lung of localized pleuropulmonary diseases, including primary lung cancer and pleural thickening, and in both lungs in cases of heart diseases, diffuse pulmonary diseases including diffuse interstitial pneumonia and diffuse panbronchiolitis. The sum of (E-I)/I(+) of the both lungs, which correlated with vital capacity and PaO2, showed a decrease in diffuse interstitial pneumonia, pulmonary emphysema, diffuse panbronchiolitis, primary lung cancer, pleural diseases and so on. (E-I)/I(+), correlated with pulmonary perfusion (n = 49, r = 0.51, p less than 0.001), but not a few cases showed mismatch, which was observed in primary lung cancer, pleural diseases, pulmonary emphysema, diffuse panbronchiolitis and so on. (E-I)/I(+) better correlated with pulmonary ventilation by ventilation scintigraphy with 81mKr or 133Xe (n = 49, r = 0.61, p less than 0.001) than pulmonary perfusion. The ventilatory lung motion imaging, which demonstrates the motion of the intra-pulmonary areas and lung edges, appears useful for estimating pulmonary ventilation of the perfused area as well as pulmonary perfusion.     

A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with increased mortality in up to 10% of patients with rheumatoid arthritis. Lung exposure to cigarette smoke has been implicated in disease development. Little is known about the mechanisms underlying the development of RA-ILD, in part due to the lack of an appropriate mouse model. The objectives of this study were (i) to test the suitability of SKG mice as a model of cellular and fibrotic interstitial pneumonia in the setting of autoimmune arthritis, and (ii) to determine the role of lung injury in the development of arthritis in SKG mice. Lung tissues were evaluated in arthritic SKG mice by quantifying cell accumulation in bronchoalveolar lavage, static compliance, collagen levels, and infiltrating cell phenotypes by flow cytometry and histology. Lung injury was induced by exposure to cigarette smoke or bleomycin. Arthritic SKG mice developed a patchy cellular and fibrotic interstitial pneumonia associated with reduced static compliance, increased collagen levels, and accumulation of inflammatory cells. Infiltrating cells comprised CD4+ T cells, B cells, macrophages, and neutrophils. Chronic exposure to cigarette smoke or initiation of lung injury with bleomycin did not cause arthritis. The pattern of lung disease suggests that arthritic SKG mice represent an authentic model of nonspecific interstitial pneumonia in RA-ILD patients. The lack of arthritis development after cigarette smoke or lung injury suggests that a model where breaches in immunologic tolerance are induced by lung inflammation and injury alone may be overly simplistic.     

Advances in the treatment of rheumatic interstitial lung disease

PURPOSE OF REVIEW: Interstitial lung disease frequently complicates the rheumatic diseases. The purpose of this review is to outline recent advances and current concepts regarding the management of these interstitial lung diseases. RECENT FINDINGS: Several histologic lesions cause interstitial lung disease in rheumatic diseases, including nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, and acute interstitial pneumonia. Although the relative frequency of occurrence of these histopathologic lesions is not definitively established, it seems that nonspecific interstitial pneumonia accounts for a large proportion of rheumatic disease-associated interstitial lung diseases. Although usual interstitial pneumonia generally responds poorly to corticosteroid therapy, other forms of interstitial pneumonia are often steroid responsive and have a more favorable long-term prognosis. Pulmonary hypertension is increasingly recognized as a complication of these interstitial lung diseases. Treatment of pulmonary hypertension in these patients provides clinical benefit and may suppress pulmonary inflammation and fibrosis. Lung transplantation is a treatment option for selected patients with severe pulmonary involvement and limited life expectancy. SUMMARY: Interstitial lung disease is common in the rheumatic diseases, may be caused by a variety of lesions that respond differently to treatment, and may lead to the development of pulmonary hypertension. Whether the prognosis of interstitial lung disease associated with rheumatic disease is similar to that associated with the idiopathic interstitial pneumonias is not known. Treatment of these interstitial lung diseases should take into account the specific histologic lesion, the activity of the underlying rheumatic disease, and associated pulmonary hypertension, if present. The diagnosis of a rheumatic disease is no longer an absolute contraindication to lung transplantation.     

Endothelial cell damage and tubuloreticular structures in interstitial lung disease associated with collagen vascular disease and viral pneumonia

Lung tissue showing the light microscopic changes of interstitial inflammation and fibrosis was studied electron-microscopically in 11 patients with collagen vascular disease and 26 patients with viral pneumonia. All patients exhibited progressive respiratory insufficiency and had abnormal pulmonary function test results. Endothelial cell cytoplasmic swelling and intracellular tubuloreticular structures were the dominant ultrastructural change in the lungs of both groups. Tubuloreticular structures were identified in peripheral blood lymphocytes in all patients with collagen vascular disease and in 2 with viral pneumonia. Tubuloreticular structures were not identified in the lung tissue from various control patients and in the lymphocytes from patients with idiopathic interstitial pulmonary fibrosis. We conclude that (1) the ultrastructural changes seen in viral pneumonia and collagen vascular-associated interstitial lung disease are essentially identical; (2) endothelial cell damage may be the primary pathologic change associated with both diseases; (3) tubuloreticular structures are seen in large numbers in lung tissue from patients with viral pneumonia and collagen vascular disease; (4) tubuloreticular structures are present in peripheral blood lymphocytes from all patients with collagen vascular disease.     

The pathology of smoking-related lung diseases

A broad range of non-neoplastic pulmonary lesions is associated with cigarette smoking including airway diseases with airflow limitation, vascular alterations and interstitial lung diseases characterized by diffuse radiographic abnormalities and restricted lung volumes. This article focuses on the pathology of smoking-related emphysema, alterations of large airways, alterations of pulmonary vessels, respiratory bronchiolitis associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), and eosinophilic granuloma (EG).     

Small cell lung cancer associated with systemic sclerosis

A 51-year-old woman developed small cell lung cancer (SCLC). She was a non-smoker and had interstitial pneumonia associated with systemic sclerosis (SSc). Sixteen additional cases obtained from the literature describing patients with SCLC associated with SSc are reviewed. The majority of patients were women with underlying interstitial pneumonia. In 3 patients who were non-smokers, interstitial pneumonia was complicated and cancer had developed in the peripheral lung field but not in the central lung field. Since SCLC is very rare in non-smokers, these findings suggest a positive association between SCLC and interstitial pneumonia associated with SSc.     

Three cases of non-specific interstitial pneumonia associated with primary lung cancer

NSIP associated with primary lung cancer has been rarely reported. In the present report, three cases of histologically proven non-specific interstitial pneumonia (NSIP) associated with primary lung cancer are described. Importantly, in our 3 cases, interstitial pneumonia which is histologically proven to be NSIP was observed diffusely in both lungs. NSIP in these 3 cases responded to steroid therapy. However, 2 patients died from primary lung cancer and 1 patient died from progression of the interstitial pneumonia. Although the association between lung cancer and NSIP has been rarely documented, this combination was considered to be one of the paraneoplastic phenomena. The possible association between primary lung cancer and NSIP is discussed.     

Lack of evidence for a role of Epstein-Barr virus in the increase of lung cancer in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is known as an independent risk factor for lung cancer. Because Epstein-Barr virus (EBV) may be involved in the genesis of IPF as well as certain malignancies, we investigated whether EBV contributes to the increased incidence of lung cancer in IPF The formalin-fixed and paraffin-embedded lung sections were prepared from 22 lung cancer patients with IPF and 22 lung cancer patients without IPF All ofthe IPF patients pathologically showed usual interstitial pneumonia. In situ hybridization for EBV-encoded small non-polyadenylated RNAs failed to show positive signals in the cancer tissues of either IPF or non-IPF patients. This study did not provide evidence for an etiologic role of EBV in the development of lung cancer in IPF.     

Role of quantitative CT in predicting hypoxemia and complications after lung lobectomy for cancer, with special reference to area of emphysema

STUDY OBJECTIVES: To determine the ability of quantitative CT, with special reference to area of emphysema, to predict early postoperative oxygenation capacity and outcome after lung lobectomy for cancer. METHODS: Sixty-two consecutive patients scheduled to undergo lung lobectomy for cancer were enrolled in this study. The area of emphysema (< - 910 Hounsfield units) was measured on a three-dimensional CT lung model. Arterial oxygen saturation (Sao(2)) was calculated from Pao(2) measured 1 day before and 1 day after surgery with patients at rest breathing room air. A patient was considered to have recovered at the completion of a standardized management regimen. RESULTS: Postoperative Sao(2) (postSao(2)) was predicted by the baseline value and the area of emphysema with the use of a regression equation. Ten of the 62 patients (16%) had postoperative cardiopulmonary complications (CPCs). The median time to postoperative recovery was 3 days (range, 1 to 17 days). Predicted postSao(2) and predicted postoperative FEV(1) were shown to be significant independent predictors of postoperative CPCs as well as postoperative recovery time. CONCLUSION: Determining the area of emphysema by quantitative CT is useful in predicting early postoperative oxygenation capacity. Predicted oxygenation capacity and predicted ventilatory capacity independently affect perioperative outcomes. Therefore, using quantitative CT in combination with spirometry may improve risk prediction in patients undergoing lung lobectomy for cancer. However, the role of quantitative CT in grading nonemphysematous lung diseases, such as interstitial lung diseases, must be investigated.     

Cytomegalovirus associated neonatal pneumonia and Wilson-Mikity syndrome: a causal relationship?

Lung injury caused by intrauterine inflammation has recently been strongly implicated in the pathogenesis of Wilson-Mikity syndrome (WMS). This article supports this theory by suggesting a causative role of intrauterine cytomegalovirus (CMV) infection for the development of WMS. A male premature infant, born at 33 weeks of gestational age, developed chronic lung disease compatible with WMS and diagnostic evaluation was positive for CMV infection. High-resolution computed tomography scan and lung histology revealed typical features of WMS in association with signs of interstitial pneumonia. CMV was found in urine, breastmilk, bronchoalveolar lavage material and lung tissue from open lung biopsy. Follow-up after treatment with ganciclovir and steroids showed resolving lung disease at the age of 6, 10 and 16 months, with lung function signs of mild obstruction. Assuming that a chance coexistence of cytomegalovirus pneumonia and Wilson-Mikity syndrome is rather unlikely, it is possible that intrauterine cytomegalovirus infection caused a pattern of lung injury consistent with Wilson-Mikity syndrome. Further cases of Wilson-Mikity syndrome should be investigated as to a possible role of congenital infection.     

The effect of emphysema on lung function and survival in patients with idiopathic pulmonary fibrosis

Background and objective: In this study the prevalence, lung function and prognosis of IPF combined with emphysema were evaluated. Methods: Consecutive patients with usual interstitial pneumonia (UIP) on high‐resolution computed tomography (HRCT), with or without emphysema, were assessed retrospectively. The area of fibrosis in the base of the lungs was assessed by HRCT as minimal (<2 cm from the subpleura), moderate (≥2 cm from the subpleura, <1/3 of the area of the base of the lungs) or severe (≥1/3 of the area of the base of the lungs). Results: Among 660 patients with UIP on HRCT, 221 showed upper‐lobe emphysema. Pulmonary function results for patients with UIP and UIP/emphysema, respectively, were: FVC, 71.8% and 87.1%; FEV1%, 86.7% and 87.9%; and DL_CO, 74.3% and 65.2% of predicted. The relationship between FVC, the extent of fibrosis and survival was investigated in 362 patients with records of pulmonary function tests and no lung cancer at the time of entry into the study. Although the extent of fibrosis was similar between the groups, 71.3% of UIP patients met the lung volume criteria for IPF (FVC <80% of predicted), whereas only 26.5% of UIP/emphysema patients met the lung volume criteria for IPF. Median survival was 7.5 years in the UIP group and 8.5 years in the UIP/emphysema group. Conclusions: Emphysema was a common finding in patients with UIP. Patients with UIP and emphysema had greater lung volumes and better survival compared with those with UIP alone.     

A case of polymyositis complicated with interstitial pneumonitis and pneumomediastinum

Pneumomediastinum as a complication of interstitial pneumonia with leakage of air into the mediastinum or subcutaneous tissues is a rare complication of dermatomyositis (DM). Herein we report a case of pneumomediastinum complicating polymyositis (PM), which is usually associated with DM. A 61-year-old man was hospitalized in our department because of deterioration of interstitial pneumonia. Treatment with high-dose corticosteroid and cyclosporin A steadily improved his interstitial pneumonia. Two weeks later, he developed subcutaneous emphysema and chest X-ray showed pneumomediastinum. Both subcutaneous emphysema and pneumomediastinum improved gradually without any additional treatment.     

Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias.

Interstitial pneumonias have recently been associated with mutations in the gene encoding surfactant protein C (SFTPC). In particular, SFTPC mutations have been reported in a number of familial forms of pulmonary fibrosis and in infants with interstitial lung diseases. The present study searched for SFTPC mutations in adult patients with sporadic idiopathic interstitial pneumonia. In total, 35 adult patients with sporadic idiopathic interstitial pneumonia and 50 healthy subjects were investigated for SFTPC mutations by direct DNA sequencing. Of the patients with sporadic idiopathic interstitial pneumonia, 25 suffered from idiopathic pulmonary fibrosis and 10 patients from nonspecific interstitial pneumonia. Only two frequent nonsynonymous variants, T138N and S186N, were detected. Allele frequencies of both variations as well as of other identified noncoding alterations did not differ significantly between the diverse patient groups and control subjects. In conclusion, mutations in the gene encoding surfactant protein C are not common in sporadic cases of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia, suggesting that the mutated gene does not play an important role in the pathogenesis of these forms of idiopathic interstitial pneumonia.