Idiopathic pulmonary fibrosis (IPF), ie, usual interstitial pneumonia in histopathology, is a disease characterized by tissue destruction and active areas of fibroproliferation in the lung. Gremlin (Drm), a member of the cysteine knot family of bone morphogenetic protein (BMP) inhibitors, functions to antagonize BMP-4-mediated signals during lung development. We describe here consistent overexpression of gremlin in the lung interstitium of IPF patients. Quantitative real-time reverse transcriptase-polymerase chain reaction analyses revealed considerably higher levels of gremlin mRNA in lung biopsies from IPF patients, the highest level being 35-fold higher compared to controls. Lung fibroblasts isolated from IPF patients also expressed elevated levels of gremlin, which was associated with impaired responsiveness to endogenous and exogenous BMP-4. Transforming growth factor--induced epithelial-tomesenchymal transition of A549 lung epithelial cells in culture was also associated with induction of gremlin mRNA expression. In addition, A549 cells transfected to overexpress gremlin were more susceptible to transforming growth factor--induced epithelial-to-mesenchymal transition. Gremlin-mediated inhibition of BMP-4 signaling pathways is likely to enhance the fibrotic response and reduce epithelial regeneration in the lung. The overexpression of this developmental gene in IPF may be a key event in the persistence of myofibroblasts in the lung interstitium and provides a potential target for therapeutic intervention. (Am J
Rationale: Members of the transforming growth factor (TGF)-b superfamily, including TGF-bs and bone morphogenetic proteins (BMPs), are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the BMP antagonist, gremlin, is highly up-regulated in idiopathic pulmonary fibrosis (IPF). Objectives: To investigate the role of gremlin in the regulation of BMP signaling in pulmonary fibrosis. Methods: Progressive asbestos-induced fibrosis in the mouse was used as a model of human IPF. TGF-b and BMP expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of gremlin induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of gremlin inhibition was tested by administration of BMP-7 to mice after asbestos exposure. Measurements and Main Results: Gremlin mRNA levels were upregulated in the asbestos-exposed mouse lungs, which is in agreement with the human IPF biopsy data. Down-regulation of BMP signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced gremlin expression could be prevented by inhibitors of the TGF-b receptor and also by inhibitors of the mitogenactivated protein kinase kinase/extracellular signal-regulated protein kinase pathways. BMP-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice. Conclusions: The TGF-b and BMP signaling balance is important for lung regenerative events and is significantly perturbed in pulmonary fibrosis. Rescue of BMP signaling activity may represent a potential beneficial strategy for treating human pulmonary fibrosis.
Transforming growth factor-betas (TGF-beta) regulate a wide variety of cellular functions in normal development and are involved in both tissue homeostasis and disease pathogenesis. The regulation of the TGF-beta family of growth factors is unique because they are targeted to the extracellular matrix in a biologically inactive form. The release from pericellular matrices and the activation of TGF-beta are important mechanisms in several pathophysiologic conditions. Reactive oxygen species (ROS) can activate TGF-beta either directly or indirectly via the activation of proteases. In addition, TGF-beta itself induces ROS production as part of its signal-transduction pathway. The lung is a unique organ, because its structures act as boundaries between gaseous and aqueous phases, allowing the utilization of inhaled oxygen. However, this renders pulmonary tissues vulnerable to the toxic effects of inhaled air. The oxidant pathways are especially relevant in the lung, where TGF-beta is known to have a role in tissue repair and connective tissue turnover. In pulmonary fibrosis, TGF-beta activation is considered as a hallmark of disease progression. More recently, the oxidative effects of cigarette smoking have been found to activate TGF-beta in chronic obstructive pulmonary disease (COPD), a disease consisting of emphysema, airway fibrosis, and focal lung fibrosis.
BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive disease with median survival from 2 to 7 years. Palliative care is an important part of patients´ care as lung transplantation is not an option for the majority of patients. The aim of this study was to describe treatment practices, decision-making and symptoms during end-of-life care of IPF patients.MethodsWe identified 59 deceased patients from a national prospective IPF cohort study (FinnishIPF) and analyzed retrospectively their health care documentation during the 6 months that preceded death.ResultsHospital was the place of death for 47 patients (80 %). A majority of the patients (93 %) were hospitalized for a mean of 30 days (range 1–96 days) during the last 6 months of their life. Altogether, patients spent 15 % of their last 6 months of life in a hospital. End-of-life decisions and do not resuscitate (DNR) orders were made for 19 (32 %) and 34 (57 %) of the patients, respectively, and 22 (42 %) of these decisions were made ≤ 3 days prior to death.During the final hospital stay, antibiotics were given to 79 % and non-invasive ventilation to 36 % of patients. During the last 24 h of life, radiologic imaging or laboratory tests were taken in 19 % and 53 % of the hospitalized patients, respectively. These tests and life prolonging therapies were more common in tertiary hospitals compared to other places of death. Dyspnea (66 %) and pain (31 %) were the most common symptoms recorded. Opioids were prescribed to 71 % of the patients during the last week before death.ConclusionsThe majority of IPF patients died in a hospital with ongoing life-prolonging procedures until death. The frequent use of opioids is an indicator of an intention to relieve symptoms, but end-of-life decisions were still made very late. Early integrated palliative care with advance care plan could improve the end-of-life care of dying IPF patients.
Estrogen-based drug therapy in cardiovascular diseases has been difficult because it has not been possible to separate the wanted vasculoprotective effect from the unwanted effects of the hormone to the reproductive system. Here, we demonstrate that, after endothelial denudation of rat carotid artery, the mRNA of the classical estrogen receptor (ER␣) is constitutively expressed at a low level whereas the expression of the novel ER mRNA increases >40-fold. Under in situ hybridization and immunohistochemistry, ER mRNA and protein colocalize with the smooth muscle cells in the media and neointima. Treatment of ovariectomized female rats with the isof lavone phytoestrogen genistein, which shows 20-fold higher binding affinity to ER than to ER␣, or with 17-estradiol, which does not differentiate between the two receptors, provides similar dosedependent vasculoprotective effect in rat carotid injury model. In addition in concentrations <10 M, both ligands are equally inhibitory to the replication and migration of smooth muscle cells in vitro. However, only treatment with 17-estradiol, but not with genistein, is accompanied with a dose-dependent uterotrophic effect. The results suggest that preferential targeting to ER will provide vasculoprotective estrogen analogs devoid of effects to the reproductive system. Vascular intimal dysplasia and remodeling are characteristic features of injury after percutaneous transluminal coronary angioplasty (1) and in chronic allograft rejection (2, 3). The initial response to injury is inflammatory and involves the attraction of lymphocytes, macrophages, and thrombocytes to the site of injury and the secretion of cytokines, eicosanoids, and growth factors (4). Under the influence of growth factors and cytokines, smooth muscle cells (SMCs) proliferate and migrate into the intima and contribute to intimal hyperplasia and vascular stenosis.Estrogen has several protective effects on the vascular wall. Some of these are rapid, presumably direct membrane effects whereas others require transcriptional activation of genes (5, 6). The inhibitory effect of estrogen on the replication, migration, and extracellular matrix deposition by vascular SMC, the key events in vascular fibroproliferative dysplasias, is presumably a genomic effect mediated through a variety of mechanisms, including regulation of several growth factors and͞or their receptors and possibly by a direct antiproliferative effect of estrogen on SMC (5, 7).The development of vasculoprotective drug therapies based on the protective effect of estrogen has been difficult, as it has not been possible to differentiate the desired vasculoprotective effect of estrogen from its effects on the reproductive system. In this communication, we demonstrate that this is possible by preferential targeting to the novel estrogen receptor  (ER). MATERIALS AND METHODSCarotid Denudation Injury. Carotid denudations were made to Wistar rats purchased from the Laboratory Animal Center (University of Helsinki). The details of the operation...
Disruption of the oxidant/antioxidant balance in the lung is thought to be a key step in the development of many airway pathologies. Hence, antioxidant enzymes play key roles in controlling or preventing pulmonary diseases related to oxidative stress. The superoxide dismutases (SOD) are a family of enzymes that play a pivotal role protecting tissues from damage by oxidant stress by scavenging superoxide anion, which prevents the formation of other more potent oxidants such as peroxynitrite and hydroxyl radical. Extracellular SOD (EC-SOD) is found predominantly in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. EC-SOD has been shown to be protective in several models of interstitial lung disease, including pulmonary fibrosis. In addition, alterations in EC-SOD expression are also present in human idiopathic pulmonary fibrosis (IPF). This review discusses EC-SOD regulation in response to pulmonary fibrosis in animals and humans and reviews possible mechanisms by which EC-SOD may protect against fibrosis.
Our results clearly indicate that several markers of oxidative/nitrosative stress are increased in current cigarette smokers compared to non-smokers and no major differences can be observed in these biomarkers between non-symptomatic smokers and subjects with GOLD stage 0 COPD.
Chronic Obstructive Pulmonary Disease (COPD), a lung disease related to smoking, is one of the leading causes of chronic morbidity and mortality around the world. One goal in COPD research is the identification of biomarkers for early diagnosis of the disease. Here, we sought COPD-specific changes in the proteome from human lung tissue. This revealed increased levels of surfactant protein A (SP-A) in COPD but not in the normal or fibrotic lung. The results were confirmed by immunohistochemistry, morphometry and Western blotting. Furthermore, elevated SP-A protein levels were detected from the induced sputum supernatants of COPD patients. The levels of other surfactant proteins (SP-B, SP-C, SP-D) were not altered. Our results suggest that SP-A is linked to the pathogenesis of COPD and could be considered as a potential COPD biomarker.
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