Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases

Usual interstitial pneumonia is an almost uniformly fatal form of fibrosing interstitial lung disease. It is the most common idiopathic interstitial pneumonia, and currently, there is no effective therapy. Lung biopsy is often needed for diagnosis, and pathologists must be able to recognize its features and distinguish it from other interstitial lung diseases that have a better prognosis and a more favorable response to therapy. This review is an attempt to clarify the diagnostic pathologic features of usual interstitial pneumonia and to provide guidelines for its distinction from other interstitial lung diseases that enter the differential diagnosis.     

硫氧还蛋白还原酶在大鼠阿尔茨海默病模型海马结构中的表达

目的 :探讨硫氧还蛋白还原酶 (thioredoxinreductase,TR)在阿尔茨海默病 (Alzheimer′sDisease,AD)大鼠模型发生中的作用。方法 :注射海人藻酸 (Kainicacid ,KA)毁损Meynert基底核建立AD大鼠模型 ,通过Y形迷宫判断动物模型成功与否 ,采用原位杂交方法检测AD大鼠模型中TRmRNA的表达。结果 :AD模型组大鼠短期学习记忆能力与对照组相比明显下降 (P <0 0 0 1 ) ,说明AD动物模型建立成功 ;TRmRNA原位杂交检测显示模型组大鼠海马各区TRmRNA杂交信号显著增强 ,与对照组相比有显著差异 (P <0 0 0 1 )。结论 :TR在AD发生发展中可能起神经元保护作用     

Familial interstitial lung disease and new insights on molecular biology and pathogenesis

Familial idiopathic pulmonary fibrosis is defined as interstitial fibrosis affecting two or more family members, and constitutes 2–20% of all cases of idiopathic pulmonary fibrosis. Investigation of the genetics of familial idiopathic interstitial fibrosis will hopefully provide insight into pathogenesis as well as provide potential targets for therapy. Telomerase mutations, mutations of surfactant genes and mutations of MUC5B have been most commonly reported. However, 80% of familial cases remain without an identifiable mutation, and pathogenesis remains poorly understood. A shift away from an inflammatory driven pathogenesis to one of abnormal wound healing has occurred, with injury to alveolar epithelium and aberrant fibroproliferation likely underlying the process. Such aberrant wound healing likely occurs in a background of genetic predisposition and exposure to environmental stressors. An additional theory of traction related injury has also been proposed.     

Cell-specific regulation of gamma-glutamylcysteine synthetase in human interstitial lung diseases

The pathogenesis of interstitial lung diseases (ILDs) is known to be associated with reactive oxygen and nitrogen metabolites and increased oxidant stress. One of the major antioxidants in human lung is glutathione (GSH) and enzymes linked to its synthesis. The rate-limiting enzyme of GSH synthesis is gamma-glutamylcysteine synthetase (γ-GCS) containing catalytically active heavy (γ-GCSh) and regulatory light (γ-GCSl) subunits. It can be hypothesized that γ-GCS is the major determinant in explaining reduced GSH levels in fibrotic lung disorders. We investigated the regulation of γ-GCS by transforming growth factor beta₁ (TGF-β₁) and tumor necrosis factor alpha (TNF-α) in human lung cells and its expression and distribution in fibrotic (biopsy-proven idiopathic pulmonary fibrosis, for instance, usual interstitial pneumonia, UIP, n = 15), inflammatory, and granulomatous diseases of human lung parenchyma (desquamative interstitial pneumonia, n = 10; ILD associated with collagen diseases, n = 10; sarcoidosis, n = 19 and allergic alveolitis, n = 8). In human lung alveolar epithelial cells, γ-GCSh was decreased by TGF-β₁, whereas TNF-α caused a transient enzyme induction. In normal lung, γ-GCS was mainly localized to the bronchiolar epithelium. In UIP, the highest immunoreactivities were observed in the airway epithelium and metaplastic alveolar epithelium, but fibroblastic foci were negative. In sarcoidosis, the highest reactivities were detected in the epithelium, alveolar macrophages and pulmonary granulomas. γ-GCS was ultrastructurally localized to the cytoplasm of regenerating type II pneumocytes and macrophages. In conclusion, γ-GCS is widely expressed in sarcoidosis and regenerating epithelium but is low in the fibrotic areas of usual interstitial pneumonia, probably because of enzyme down-regulation.     

Beyond a consensus classification for idiopathic interstitial pneumonias: progress and controversies

Histopathological classification schemes provide the underpinnings for separating idiopathic interstitial pneumonias into clinically meaningful groups. An interdisciplinary classification system based on a combination of evidence and expert opinion was published in 2002 and set the stage for controversy in several areas, including not only nomenclature but also the role of surgical lung biopsy and pathologists in diagnosis. We provide a brief overview of the clinical and histological features of the idiopathic interstitial pneumonias, and focus on selected topics of interest that have emerged in recent years.     

Acute exacerbations of fibrotic interstitial lung disease

Churg A, Wright J L & Tazelaar H D
(2011) Histopathology  58 , 525–530
Acute exacerbations of fibrotic interstitial lung disease An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre‐existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non‐specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high‐dose steroid therapy.     

Desquamative interstitial pneumonia in sibs

We report on 2 sibs with desquamative interstitial pneumonia. The female died at age 1 7/12 years despite use of prednisolone and methylprednisolone, while the male, now age 3 years, is alive with oxygen support. The occurrence of desquamative interstitial pneumonia in sibs born to normal parents suggests that in some cases the disease is an autosomal-recessive trait. © 1995 Wiley-Liss, Inc.     

AKR1B10 in usual interstitial pneumonia: expression in squamous metaplasia in association with smoking and lung cancer

The incidence of lung cancer (LC) is markedly increased among patients with usual interstitial pneumonia (UIP), and tobacco smoking is its superimposed risk factor. AKR1B10 (aldo-keto reductase 1B10) is frequently overexpressed in pulmonary squamous cell carcinoma and adenocarcinoma in smokers. To investigate the role of AKR1B10 in the pulmonary carcinogenesis in UIP with correlation to tobacco smoking, we examined 13 UIP cases with LC, 13 UIP cases without LC, and 30 cases of non-UIP LC using AKR1B10 immunohistochemistry. AKR1B10 immunoreactivity was confined to squamous metaplasia in honeycomb lesions of UIP and neoplastic cells of LC. Squamous metaplastic foci showed AKR1B10 immunoreactivity more frequently in UIP with LC (24/36 foci, 67%) than in UIP without LC (16/44 foci, 37%) (P<0.01). AKR1B10 expression in UIP was also more frequent in squamous metaplastic foci in smokers (38/67 foci, 57%) than in non-smokers (2/13 foci, 15%) (P<0.01). AKR1B10 expression was frequently observed in both UIP-associated LC (10/13 foci, 77%) and non-UIP LC (18/30 foci, 60%). Ki-67 labeling index was significantly higher in AKR1B10-positive squamous metaplasia of UIP than in AKR1B10-negative squamous metaplasia of UIP. Our results demonstrate that AKR1B10 is involved in the development of LC in UIP in association with smoking. AKR1B10 might be useful as a new marker for identification of high LC risk patients in UIP.     

Collagen and elastic system in the remodelling process of major types of idiopathic interstitial pneumonias (IIP)

AIMS: Structural remodelling in acute and chronic idiopathic interstitial pneumonia (IIP) has been extensively investigated, but little attention has been directed to the elastic tissue in these situations. The aim of this study was to determine whether elastic deposition accompanies collagen deposition in the four major histological patterns of IIP: diffuse alveolar damage (DAD), organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). METHODS AND RESULTS: We measured, by image analysis, the content of fibres of the collagenous and elastic systems of the alveolar septum in histological slides of open lung biopsies, using the picrosirius-polarization method and Weigert's resorcin-fuchsin stain, respectively. Five groups were studied: 10 cases of DAD; nine cases of OP; nine cases of NSIP; and 10 cases of UIP. Four normal lungs were used for comparison. The content of collagen fibres was significantly higher in UIP when compared to DAD, NSIP, OP and normal lung. The content of elastic fibres was increased in comparison with normal lungs but this was not significantly different among the histological patterns. CONCLUSION: Acute and chronic IIP cause a similar increase in the collagen and elastic contents of the lungs, representing a process of 'fibroelastosis' rather than an exclusive process of fibrosis. A profibrogenic mechanism is responsible for the unparallelled collagen augmentation observed in UIP subjects, the nature of which is yet to be determined.     

Current and emerging treatment options for interstitial lung disease in patients with rheumatic disease

The management of connective tissue disease-associated interstitial lung disease (CTD-ILD) is complex and this arena offers many challenges to the practicing clinician. Unfortunately, treatment strategies and recommendations are often based on experience rather than evidence, and there are few effective therapeutic options. Pharmacologic intervention with immunosuppression is usually the mainstay of therapy and is reserved for those with clinically significant and/or progressive ILD. There is a desperate need for controlled trials across the spectrum of CTD-ILD and a number of potentially promising novel therapies warrant further study. It is important to address co-morbid conditions or aggravating factors (e.g., gastroesophageal reflux, aspiration, bone health, pulmonary hypertension, Pneumocystis jiroveci prophylaxis) and to institute non-pharmacologic management strategies (e.g., supplemental oxygen and cardiopulmonary rehabilitation) as part of a comprehensive treatment plan in CTD-ILD.     

Novel patterns of interstitial lung disease

The 2002 ATS/ERS Idiopathic Interstitial Pneumonia Classification provided diagnostic criteria for seven well-known entities. Since then, new information has enriched our knowledge about these conditions and rare new entities have been proposed by different authors. Among these, pleuroparenchymal fibroelastosis has been recognized as a distinct clinicopathologic entity characterized by pleura and subpleural parenchymal fibrosis, predominantly composed of elastic fibres. Moreover, unusual histologic patterns, including acute fibrinous and organizing pneumonia and airway-centred interstitial fibrotic diseases, have also been described. The former is characterized by intra-alveolar fibrin deposition and associated organizing pneumonia in the absence classical hyaline membranes, while the latter includes a group of patterns remarkable for inflammation and fibrosis centred around the bronchioles. Whether these latter two patterns represent distinct entities or variants of existing idiopathic lung diseases requires further study. Since the practicing pathologists should to be aware these rare entities and patterns, this paper highlights the current knowledge about these conditions.     

Classification of idiopathic interstitial pneumonias: making sense of the alphabet soup

Since Liebow and Carrington's original classification of idiopathic interstitial pneumonias, there have been controversies over which histological patterns should be included and how they relate to clinicopathological diseases such as cryptogenic fibrosing alveolitis/idiopathic pulmonary fibrosis (CFA/IPF). Because of these differences and the wealth of overlapping terminology, a consensus classification system has been proposed, devised by a group of clinicians, radiologists and pathologists. Seven histological patterns are recognized: usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), diffuse alveolar damage (DAD), organizing pneumonia (OP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis (RB) and lymphocytic interstitial pneumonia (LIP), each with a clinicopathological counterpart, the most well defined being UIP and CFA/IPF. The system is applicable both in terms of the pathologist identifying histological patterns in isolation and in terms of the pathologist's role in contributing to the final clinicopathological diagnosis. It will probably provide greater consistency in diagnosis, early studies suggesting that the system is reproducible, and also identify purer cohorts for studies investigating causation. It also highlights the fact that the 'gold standard for diagnosis' is no longer a surgical lung biopsy in isolation but more the clinicopathological conference, when clinical, imaging and histological data are jointly discussed to produce the final clinicopathological diagnosis.     

Elevated matrilysin levels in bronchoalveolar lavage fluid do not distinguish idiopathic pulmonary fibrosis from other interstitial lung diseases

Microarray studies have shown that matrilysin or matrix metalloproteinase (MMP)-7 is highly upregulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF), but MMP-7 protein expression has not been systematically compared between IPF and other interstitial lung diseases. MMP-7 levels in bronchoalveolar lavage fluid (BALF) were compared to corresponding samples from nonspecific interstitial pneumonia (NSIP), sarcoidosis, and healthy controls. MMP-7 levels in the BALF were determined by ELISA and localization of MMP-7 in the lung tissue by immunohistochemistry. MMP-7 was similarly elevated in the BALF of all these disorders compared to healthy controls (p=0.007). Even control subjects with prolonged cough displayed a tendency towards elevated MMP-7 expression. There was a negative correlation between BALF MMP-7 levels and forced expiratory vital capacity (r=-0.348, p=0.02, n=42). In IPF lung, MMP-7 immunoreactivity appeared predominantly in the fibrotic parenchyma and arterial wall. In sarcoidosis and NSIP, prominent MMP-7 immunoreactivity was found in areas of inflammation. These results demonstrate that elevated BALF MMP-7 is not restricted to IPF alone but is also observed in other interstitial lung diseases and cannot be used as a differential diagnostic marker for IPF.     

A case of severe IgA nephropthy assocaited with psoriatic arthritis an idopathic interstitial pneumonia

A patient is described with severe IgA nephropathy associated with psoriatic arthritis, idiopathic interstitial pneumonia and brain hemorrhage that developed serially over one and a half years. The histological findings of the renal biopsy showed severe endo-and extracapillary proliferative glomerulonephritis. Massive IgA deposits were observed by immunoflurorescence not only in the mesangium but also along the capillary walls. Electron microscopy revealed abundant electron-dense deposits in the mesangial and subendothelial areas. The overlapping or coexistence of these conditions has rarely been reported.     

硬皮病相关间质性肺疾病发病机制的研究进展

间质性肺疾病是硬皮病的一种常见肺损伤,是影响硬皮病预后的主要原因。目前,尽管其发病机制不十分明确,但已取得一定的研究进展。许多研究者提出微血管损伤和免疫介导的炎症反应共同参与肺纤维化的形成,从而导致硬皮病相关间质性肺疾病的发生。其他可能机制包括胃食管反流和一些新型标志物SP-D,KL-6,小窝蛋白-1等。本文就上述方面的有关研究进展进行综述。     

Nonspecific interstitial pneumonia overlaps organizing pneumonia in lung-dominant connective tissue disease

Here, we reported two cases of nonspecific interstitial pneumonia overlap organizing pneumonia (NSIP/OP) with lung-dominant connective tissue disease (LD-ILD). The first case is a patient with hands of chapped skin, right-sided pleuritic chest discomfort, weakness, positive ANA and antibodies to Ro/SS-A (+++) and Ro-52 (++). In the second case, there were Reynaud’s disease, and nucleolus-ANA increased (1:800). Chest high resolution CT scan in both cases showed ground-glass opacifications, predominantly in basal and subpleural region and the pathologic manifestation were correlated with NSIP/OP, which were previously discovered in Sjogren syndrome, PM/DM and other rheumatic diseases. The two cases of NSIP/OP with LD-CTD we reported expand disease spectrum of NSIP/OP pathological types in ILD. However, it is necessary to process large-scale studies.