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Concept: Pulmonary fibrosis

174

Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of Mkl1 protected mice from experimental lung fibrosis. These studies indicate that targeting mechanosensitive signaling in myofibroblasts to trigger the intrinsic apoptosis pathway may be an effective approach for treatment of fibrotic disorders.

Concepts: Cancer, Signal transduction, Adenosine triphosphate, Fibrosis, Apoptosis, In vivo, Idiopathic pulmonary fibrosis, Pulmonary fibrosis

171

Extracellular matrix deposition and tissue scarring characterize the process of fibrosis. Transforming growth factor beta (TGFβ) and Insulin-like growth factor binding protein-3 (IGFBP-3) have been implicated in the pathogenesis of fibrosis in various tissues by inducing mesenchymal cell proliferation and extracellular matrix deposition. We identified Syndecan-2 (SDC2) as a gene induced by TGFβ in an IGFBP-3-dependent manner. TGFβ induction of SDC2 mRNA and protein required IGFBP-3. IGFBP-3 independently induced production of SDC2 in primary fibroblasts. Using an ex-vivo model of human skin in organ culture expressing IGFBP-3, we demonstrate that IGFBP-3 induces SDC2 ex vivo in human tissue. We also identified Mitogen-activated protein kinase-interacting kinase (Mknk2) as a gene induced by IGFBP-3. IGFBP-3 triggered Mknk2 phosphorylation resulting in its activation. Mknk2 independently induced SDC2 in human skin. Since IGFBP-3 is over-expressed in fibrotic tissues, we examined SDC2 levels in skin and lung tissues of patients with systemic sclerosis (SSc) and lung tissues of patients with idiopathic pulmonary fibrosis (IPF). SDC2 levels were increased in fibrotic dermal and lung tissues of patients with SSc and in lung tissues of patients with IPF. This is the first report describing elevated levels of SDC2 in fibrosis. Increased SDC2 expression is due, at least in part, to the activity of two pro-fibrotic factors, TGFβ and IGFBP-3.

Concepts: Signal transduction, Extracellular matrix, Fibrosis, Skin, Tissue, Idiopathic pulmonary fibrosis, Pulmonary fibrosis, Scleroderma

169

Pirfenidone (PFD) is a novel antifibrotic agent approved for patients with pulmonary fibrosis. However, there are concerns regarding toxicity of the drug. In this meta-analysis, we analyzed the adverse events (AEs) of PFD for the treatment of pulmonary fibrosis.

Concepts: Pharmacology, Epidemiology, Fibrosis, Randomized controlled trial, Pharmaceutical industry, Idiopathic pulmonary fibrosis, Pulmonary fibrosis

168

BACKGROUND: Stress of the endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR) and alveolar epithelial cell (AEC) apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18) is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker. METHODS: IPF and normal lung tissues were stained with the antibody (M30) that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP), nonspecific interstitial pneumonia (NSIP), and control subjects. RESULTS: cCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1alpha and spliced XBP-1) were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1alpha and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome. CONCLUSIONS: cCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker.

Concepts: Immune system, Pulmonology, Lung, Endoplasmic reticulum, Epithelium, Idiopathic pulmonary fibrosis, Pulmonary fibrosis, Unfolded protein response

147

There is currently no effective treatment for acute exacerbation of idiopathic pulmonary fibrosis (IPF). We herein report the case of a patient with acute exacerbation of IPF which was treated with nintedanib, an intracellular inhibitor of tyrosine kinases, and showed improvement of the condition. An 84-year-old man with IPF was admitted to our hospital because of dry cough and worsening of dyspnoea within last 1 month. He presented with hypoxemia, and chest high-resolution computed tomography (HRCT) revealed new, bilateral multifocal ground-glass opacities superimposed on the background of lung fibrosis. After exclusion of alternative causes, acute exacerbation of IPF was diagnosed and we started treatment with nintedanib of 300 mg/day. This resulted in the gradual improvement of his condition and HRCT findings without administering antibiotics or corticosteroids. Serum Krebs von den Lungen-6 and surfactant protein D levels increased at acute exacerbation and subsequently decreased. This case suggests that nintedanib therapy may have possible benefits in acute exacerbation of IPF.

Concepts: Signal transduction, Asthma, Pneumonia, Fibrosis, Idiopathic pulmonary fibrosis, Pulmonary fibrosis, Bronchitis, Sarcoidosis

147

Idiopathic pulmonary fibrosis (IPF) is a rare and fatal restrictive respiratory disease under the idiopathic lung disease (ILD) class. IPF is a form of chronic, progressive fibrosing interstitial pneumonia and has more scarring, less inflammation, and poorer prognosis than most other ILD forms. Exacerbation of IPF is rapid, with unpredictable deterioration of lung function, and is associated with short-term mortality. The American Thoracic Society (ATS) evidence-based guidelines for diagnosis and management of IPF reports that the incidence of acute exacerbations is between 5%-10%. Limited real-world evidence has been identified in the United States that assesses patterns of hospitalization, exacerbation of IPF, and the associated economic burden.

Concepts: Pulmonology, Asthma, Lung, Medical terms, Pneumonia, Fibrosis, Idiopathic pulmonary fibrosis, Pulmonary fibrosis

146

In humans, horses, and rodents, an association between pulmonary fibrotic disorders and gammaherpesvirus infection has been suggested. In dogs, canine idiopathic pulmonary fibrosis (CIPF), a progressive fibrotic lung disease of unknown origin and poorly understood pathophysiology, has been reported to occur in West Highland white terriers (WHWTs). The present study investigated the potential association between CIPF and herpesvirus infection. A PCR assay, using a mixture of degenerate and deoxyinosine-substituted primers targeting highly conserved regions of the DNA polymerase gene (DPOL) of herpesviruses, was applied on both lung and blood samples from WHWTs affected with CIPF and controls. Herpesvirus DPOL sequence could not be amplified from any of 46 lung samples (28 affected WHWTs and 18 control dogs of various breeds) and 38 blood samples (19 CIPF WHWTs and 19 control age-matched WHWTs) included. An association between CIPF and herpesvirus infection is therefore unlikely. Investigation of other causes of the disease is warranted.

Concepts: DNA, Polymerase chain reaction, Virus, Fibrosis, DNA polymerase, Idiopathic pulmonary fibrosis, Pulmonary fibrosis, West Highland White Terrier

38

Computed tomography (CT) and spirometry are the mainstays of clinical pulmonary assessment. Spirometry is effort dependent and only provides a single global measure that is insensitive for regional disease, and as such, poor for capturing the early onset of lung disease, especially patchy disease such as cystic fibrosis lung disease. CT sensitively measures change in structure associated with advanced lung disease. However, obstructions in the peripheral airways and early onset of lung stiffening are often difficult to detect. Furthermore, CT imaging poses a radiation risk, particularly for young children, and dose reduction tends to result in reduced resolution. Here, we apply a series of lung tissue motion analyses, to achieve regional pulmonary function assessment in β-ENaC-overexpressing mice, a well-established model of lung disease. The expiratory time constants of regional airflows in the segmented airway tree were quantified as a measure of regional lung function. Our results showed marked heterogeneous lung function in β-ENaC-Tg mice compared to wild-type littermate controls; identified locations of airway obstruction, and quantified regions of bimodal airway resistance demonstrating lung compensation. These results demonstrate the applicability of regional lung function derived from lung motion as an effective alternative respiratory diagnostic tool.

Concepts: Pulmonology, Asthma, Lung, Respiratory physiology, Cystic fibrosis, Pulmonary fibrosis, Spirometry

31

Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic inflammatory process, but current evidence indicates that the fibrotic response is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that induce the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of the epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The mechanisms that link idiopathic pulmonary fibrosis with ageing and aberrant epithelial activation are unknown; evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes have a role. In this Seminar, we review recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis.

Concepts: Asthma, Lung, Collagen, Extracellular matrix, Fibrosis, Epithelium, Idiopathic pulmonary fibrosis, Pulmonary fibrosis

29

Idiopathic pulmonary fibrosis is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix causing lung distortions and dysfunctions. The prognosis after detection is merely 3-5 years and the only two Food and Drug Administration-approved drugs treat the symptoms, not the disease, and have numerous side effects. Stem cell therapy is a promising treatment strategy for pulmonary fibrosis. Current animal and clinical studies focus on the use of adipose or bone marrow-derived mesenchymal stem cells. We, instead, have established adult lung spheroid cells (LSCs) as an intrinsic source of therapeutic lung stem cells. In the present study, we compared the efficacy and safety of syngeneic and allogeneic LSCs in immuno-competent rats with bleomycin-induced pulmonary inflammation in an effort to mitigate fibrosis development. We found that infusion of allogeneic LSCs reduces the progression of inflammation and fibrotic manifestation and preserves epithelial and endothelial health without eliciting significant immune rejection. Our study sheds light on potential future developments of LSCs as an allogeneic cell therapy for humans with pulmonary fibrosis. Stem Cells Translational Medicine 2017.

Concepts: Pulmonology, Fibrosis, Stem cell, Mesenchymal stem cell, Bone marrow, Stem cells, Idiopathic pulmonary fibrosis, Pulmonary fibrosis