This study of twelve patients focused on a variant of cryptogenic organizing pneumonia (COP) labeled the cicatricial form in which the airspaces of the lung are filled with and consolidated by dense ...collagenized scar tissue associated with preservation of underlying lung architecture. Patients were predominantly middle aged men and presented with bilateral lung disease in the majority of cases, often with nodular or reticulonodular disease (10/12; 83%). Patients were usually symptomatic with shortness of breath, cough, and dyspnea on exertion. Fifty-five percent of patients (6/11) had persistent or progressive disease at follow-up (mean: 68.5 months; median: 110 months). The cicatricial variant of cryptogenic organizing pneumonia may be predictive of a more recalcitrant form of COP that needs to be morphologically separated from classical COP, usual interstitial pneumonia and nonspecific interstitial pneumonia.
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. ...Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear.
Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1(-/-) mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema.
We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.
The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant ...recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial.
We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA).
We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 4.53 to 9.59; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 3.48 to 9.52; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 4.91 to 19.78; p < 0.001).
Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.
The parietal pleura is often biopsied in patients with idiopathic pleural effusion, and in up to 40% of cases, a diagnosis of nonspecific pleuritis/fibrosis (NSP) is rendered. The histology of this ...reaction has not been well described including a pattern of B cell lymphoid hyperplasia described as “chronic follicular pleuritis (CFP)”. Thirty-two cases of NSP were studied, of which 13 (41%) corresponded to CFP with the remainder displaying a fibrinous and organizing pleuritis with varying degrees of collagenization. CFP had similar etiologies as NSP with long term follow-up, including cardiac disease, pericarditis, asbestos exposure, and occult malignancy. The importance of recognizing a previously undescribed B cell/plasma cell pleural inflammatory response in reactive pleural disease is discussed.
•Thirty-two cases of clinical “nonspecific pleuritis” were studied.•Thirteen of 32 cases were chronic follicular pleuritis.•Chronic follicular pleuritis had similar etiologies as “nonspecific pleuritis”.•The histopathology of chronic follicular pleuritis is described.
In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 ...by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.
Pathobiology of severe asthma Trejo Bittar, Humberto E; Yousem, Samuel A; Wenzel, Sally E
Annual review of pathology,
01/2015, Letnik:
10
Journal Article
Recenzirano
Severe asthma (SA) afflicts a heterogeneous group of asthma patients who exhibit poor responses to traditional asthma medications. SA patients likely represent 5-10% of all asthma patients; however, ...they have a higher economic burden when compared with milder asthmatics. Considerable research has been performed on pathological pathways and structural changes associated with SA. Although limitations of the pathological approaches, ranging from sampling, to quantitative assessments, to heterogeneity of disease, have prevented a more definitive understanding of the underlying pathobiology, studies linking pathology to molecular markers to targeted therapies are beginning to solidify the identification of select molecular phenotypes. This review addresses the pathobiology of SA and discusses the current limitations of studies, the inflammatory cells and pathways linked to emerging phenotypes, and the structural and remodeling changes associated with severe disease. In all cases, an effort is made to link pathological findings to specific clinical/molecular phenotypes.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation.
To ...determine changes in expression and role of microRNAs in IPF.
RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-beta. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry.
Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-beta down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells.
Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00258544).
Summary The diagnostic entity of clear cell carcinoma of the lung (CCCL) is controversial, with many investigators arguing against its inclusion in the World Health Organization classification of ...lung carcinoma. Because of its rarity and questions regarding its histogenesis, I studied 3 groups of carcinomas with immunohistochemical and molecular assays, including 6 cases of CCCL, 7 cases of adenocarcinoma with clear cell change, and 11 cases of squamous carcinomas with prominent clear cell change. CCCL tended to be present in older individuals with an adenocarcinoma immunophenotype (cytokeratin 7 and TTF1 positivity). Molecular analysis by Sanger sequencing revealed KRAS mutations in 5 of 6 cases of CCCL, 2 of 7 adenocarcinomas with clear cell change, and 2 of 11 squamous carcinomas with clear cell change. Although perhaps not a distinct pathologic entity, in this pilot study, CCCL has an immunophenotype similar to solid-type adenocarcinoma with clear cell change and displays more frequent and unusual KRAS mutations than expected in most adenocarcinomas of the lung.
Nine cases of clinical and radiographic chronic interstitial lung disease are presented that have features of respiratory bronchiolitis-associated interstitial lung disease, but were associated with ...a respiratory bronchiolitis having extensive paucicellular lamellar eosinophilic collagenous thickening of alveolar septa in a patchy, particularly subpleural distribution. Patients were middle-aged with shortness of breath, mixed obstructive and restrictive lung disease with markedly reduced diffusing capacity and radiographs demonstrating centrilobular micronodules, occasional ground glass opacities and emphysema. All were alive at follow-up. The morphology of this process raises the differential diagnosis with the fibrotic form of nonspecific interstitial pneumonia and highlights the role of cigarette smoking as a potential cause of fibrotic lung disease.
The molecular mechanisms underlying acute exacerbations of idiopathic pulmonary fibrosis (IPF) are poorly understood. We studied the global gene expression signature of acute exacerbations of IPF.
To ...understand the gene expression patterns of acute exacerbations of IPF.
RNA was extracted from 23 stable IPF lungs, 8 IPF lungs with acute exacerbation (IPF-AEx), and 15 control lungs and used for hybridization on Agilent gene expression microarrays. Functional analysis of genes was performed with Spotfire and Genomica. Gene validations for MMP1, MMP7, AGER, DEFA1-3, COL1A2, and CCNA2 were performed by real-time quantitative reverse transcription-polymerase chain reaction. Immunohistochemistry and in situ terminal deoxynucleotidyltransferase dUTP nick end-labeling assays were performed on the same tissues used for the microarray. ELISA for alpha-defensins was performed on plasma from control subjects, patients with stable IPF, and patients with IPF-AEx.
Gene expression patterns in IPF-AEx and IPF samples were similar for the genes that distinguish IPF from control lungs. Five hundred and seventy-nine genes were differentially expressed (false discovery rate < 5%) between stable IPF and IPF-AEx. Functional analysis of these genes did not indicate any evidence of an infectious or overwhelming inflammatory etiology. CCNA2 and alpha-defensins were among the most up-regulated genes. CCNA2 and alpha-defensin protein levels were also higher and localized to the epithelium of IPF-AEx, where widespread apoptosis was also detected. alpha-Defensin protein levels were increased in the peripheral blood of patients with IPF-AEx.
Our results indicate that IPF-AEx is characterized by enhanced epithelial injury and proliferation, as reflected by increases in CCNA2 and alpha-defensins and apoptosis of epithelium. The concomitant increase in alpha-defensins in the peripheral blood and lungs may suggest their use as biomarkers for this disorder.
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