Eric B. Meltzer

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness.

Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4

Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4-null (Sdc4-/-) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4-/- mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis.

β-arrestin Deficiency Protects Against Pulmonary Fibrosis in Mice and Prevents Fibroblast Invasion of Extracellular Matrix

The signaling molecule β-arrestin is required for the fibroblast invasion of extracellular matrix and thus for the development of pulmonary fibrosis. Keeping Fibroblasts in Their Place Weeds are plants that grow unchecked in spaces where they are unwelcome, often crowding out the garden’s invited guests. Similarly, when excess connective tissue invades an unsuitable space in the body, it can have lethal consequences. This process—called fibrosis—has its place in normal physiology during wound healing. But when fibrosis occurs in the lung, for example, the displaced connective tissue built from encroaching fibroblast cells interferes with oxygen exchange, making breathing difficult to impossible. One fibrotic disease of the lung, idiopathic pulmonary fibrosis (IPF), has no known cause, as the name suggests, and no effective treatment. The authors of Lovgren et al. may now have identified the disease’s Achilles heel in a mouse model of IPF in which the lungs are chemically damaged and respond with pathological fibrosis. The new study shows that fibroblasts require the signaling protein β-arrestin to invade and degrade the extracellular matrix, and without this ability, the animals are protected from deadly lung fibrosis. Because IPF appears later in life without warning, an animal model that directly mimics the disease has not been developed. Instead, genetically tractable mice are treated with the antibiotic bleomycin and develop resulting lung fibrosis that resembles IPF. When the authors individually deleted the genes that encode each of two isoforms of β-arrestin from these bleomycin-treated mice, the animals were protected from the bleomycin-induced fibrosis, showing almost normal architecture and pliability of the lungs. These results are a major improvement, as stiffening of the normally elastic lungs is a hallmark of IPF. β-Arrestin did not contribute to lung fibrosis by participating in the inflammatory response, the authors showed, because the number or type of inflammatory cells in the lung was similar whether β-arrestin was present or not. Similarly, downstream transforming growth factor–β signaling pathways were intact. Instead, the β-arrestin was required for the behavior of the fibroblasts themselves. Although lung fibroblasts that lacked β-arrestins migrated normally toward injured lung secretions, the cells could not effectively invade the basement membrane matrix. Furthermore, these genetically modified fibroblasts displayed changes in connective tissue gene expression, likely a result of deficiencies in signaling pathways downstream of β-arrestins. The authors determined that this inability to invade also plagued fibroblasts isolated from IPF patients when β-arrestin expression was suppressed in the cells. In addition to its role in tissue invasion and deposition demonstrated here, β-arrestin participates in other signaling mechanisms that may contribute to pathogenic fibrosis. Thus, a therapeutic agent that targets this versatile signaling molecule may be useful for fighting IPF as well other fibrotic diseases. The hope is to limit fibrosis to regions where it will do more good than harm. Idiopathic pulmonary fibrosis is a progressive disease that causes unremitting extracellular matrix deposition with resulting distortion of pulmonary architecture and impaired gas exchange. β-Arrestins regulate G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors through receptor desensitization while also acting as signaling scaffolds to facilitate numerous effector pathways. Here, we examine the role of β-arrestin1 and β-arrestin2 in the pathobiology of pulmonary fibrosis. In the bleomycin-induced mouse lung fibrosis model, loss of either β-arrestin1 or β-arrestin2 resulted in protection from mortality, inhibition of matrix deposition, and protected lung function. Fibrosis was prevented despite preserved recruitment of inflammatory cells and fibroblast chemotaxis. However, isolated lung fibroblasts from bleomycin-treated β-arrestin–null mice failed to invade extracellular matrix and displayed altered expression of genes involved in matrix production and degradation. Furthermore, knockdown of β-arrestin2 in fibroblasts from patients with idiopathic pulmonary fibrosis attenuated the invasive phenotype. These data implicate β-arrestins as mediators of fibroblast invasion and the development of pulmonary fibrosis, and as a potential target for therapeutic intervention in patients with idiopathic pulmonary fibrosis.

Familial and sporadic idiopathic pulmonary fibrosis: making the diagnosis from peripheral blood

BackgroundPeripheral blood biomarkers might improve diagnostic accuracy for idiopathic pulmonary fibrosis (IPF).ResultsGene expression profiles were obtained from 89 patients with IPF and 26 normal controls. Samples were stratified according to severity of disease based on pulmonary function. The stratified dataset was split into subsets; two-thirds of the samples were selected to comprise the training set, while one-third was reserved for the validation set. Bayesian probit regression was used on the training set to develop a gene expression model for IPF versus normal. The gene expression model was tested by using it on the validation set to perform class prediction. Unsupervised clustering failed to discriminate between samples of different severity. Therefore, samples of all severities were included in the training and validation sets, in equal proportions. A gene signature model was developed from the training set. The model was built in an iterative fashion with the number of gene features selected to minimize the misclassification error in cross validation. The final model was based on the top 108 discriminating genes in the training set. The signature was successfully applied to the validation set, ROC area under the curve = 0.893, p < 0.0001. Using the optimal threshold (0.74) accurate class predictions were made for 77% of the test cases with sensitivity = 0.70, specificity = 1.00.ConclusionsBy using Bayesian probit regression to develop a model, we show that it is entirely possible to make a diagnosis of IPF from the peripheral blood with gene signatures.

Throw Caution to the Wind Instruments

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Interstitial Lung Disease

Interstitial lung diseases (ILDs), also termed diffuse parenchymal lung disease (DPLD), are a diverse group of lung diseases that can be classified according to clinical, radiologic, physiologic, or pathologic criteria that result in fibrosis of the alveolar interstitium and impairment of gas exchange. Candidate gene, genome-wide linkage, and proteomic approaches have been used to identify pathogenic antigens and genetic variants causing the ILD sarcoidosis. Mutations in surfactant proteins have been linked to familial cases of pediatric and adult interstitial pneumonia, and represent the most successful candidate gene approach to studying genetic susceptibility to DPLD. Genome-wide scanning has shown that familial forms of idiopathic interstitial pneumonias are related to several gene defects, including mutations in telomerase and mucin 5B.