Approach For Idiopathic Pulmonary Fibrosis Research Articles

ROS-Responsive Janus Au/Mesoporous Silica Core/Shell Nanoparticles for Drug Delivery and Long-Term CT Imaging Tracking of MSCs in Pulmonary Fibrosis Treatment.

Mesenchymal stem cell (MSC) therapy has been proven to be a potentially effective approach for idiopathic pulmonary fibrosis (IPF) treatment. However, this strategy is currently limited by the poor curative effect and an insufficient comprehension of the in vivo condition of the transplanted MSCs in the remedy of IPF. To address these issues, herein, a nanosystem composed of Janus Au/mesoporous silica core/shell nanoparticles (Janus NPs) is designed for effective therapeutic and real-time tracing of MSCs in MSC-based IPF therapy. The Janus NPs consist of a Au core and a pirfenidone (PFD)-loaded mesoporous silica shell asymmetrically decorated with two targeting moieties: one is reactive oxygen species (ROS)-sensitive thioketal grafted methoxy poly(ethylene glycol) (mPEG-TK), and the other is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE). The asymmetric decoration on each side of the particle allows long-term anchoring of the Janus NPs on the cell membrane to facilitate the responsive release of PFD in the ROS environment of the fibrotic lung, thereby enhancing the therapeutic efficacy of the transplanted MSCs by improving the microenvironment. Following drug release, the Janus NPs quickly enter into MSCs, achieving long-term computed tomography (CT) imaging tracing of MSCs in IPF model mice for an in-depth comprehension of the cell therapy mechanism. Overall, this work reports on Janus Au/PFD-loaded mesoporous silica core/shell NPs that combine the drug delivery and imaging tracking of MSCs, which may provide a strategy for the stem cell-based treatment of IPF.

ADAR1 Isoforms Regulate Let-7d Processing in Idiopathic Pulmonary Fibrosis.

Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2, proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d. Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lung fibroblasts. The reduction of mature Let-7d upregulates the expression of COL3A1 and SMAD2. Thus, ADAR1 isoforms and Let-7d could have a synergistic role in IPF, which is a promising explanation in the mechanisms of fibrosis development, and the regulation of both molecules could be used as a therapeutic approach in IPF.

PACS2\u2013TRPV1 axis is required for ER\u2013mitochondrial tethering during ER stress and lung fibrosis

Endoplasmic reticulum (ER) and mitochondria (mito) play a vital role in alveolar type II cell (AEC2) homeostasis and are both stressed in patients with idiopathic pulmonary fibrosis (IPF). Up to now, no data are available with regard to ER–mito cross talk and tethering under conditions of IPF. We here demonstrate that ER–mitochondrial tethering is reduced upon experimental ER stress in vitro and in the IPF AECII ex vivo, and this is—at least in part—due to decreased phosphofurin acidic cluster sorting protein 2 (PACS-2, also called PACS2) protein levels. PACS2 levels are influenced by its interaction with the transient receptor potential cation channel subfamily V member 1 (TRPV1) and can be experimentally modified by the TRPV1-modulating drug capsaicin (CPS). Employing alveolar epithelial cells with overexpression of the terminal ER stress signaling factor Chop or the IPF-associated surfactant protein C mutation (SPCΔexon4) in vitro, we observed a restoration of PACS2 levels upon treatment with CPS. Similarly, treatment of precision cut lung slices from IPF patients with CPS ex vivo forwarded similar effects. Importantly, in all models such kind of intervention also greatly reduced the extent of alveolar epithelial apoptosis. We therefore conclude that therapeutic targeting of the PACS2–TRPV1 axis represents an interesting novel, epithelial-protective approach in IPF.

Inhibition of CHIT1 as a novel therapeutic approach in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and eventually fatal lung disease with a complex etiology. Approved drugs, nintedanib and pirfenidone, modify disease progression, but IPF remains incurable and there is an urgent need for new therapies. We identified chitotriosidase (CHIT1) as new driver of fibrosis in IPF and a novel therapeutic target. We demonstrate that CHIT1 activity and expression are significantly increased in serum (3-fold) and induced sputum (4-fold) from IPF patients. In the lungs CHIT1 is expressed in a distinct subpopulation of profibrotic, disease-specific macrophages, which are only present in patients with ILDs and CHIT1 is one of the defining markers of this fibrosis-associated gene cluster. To define CHIT1 role in fibrosis, we used the therapeutic protocol of the bleomycin-induced pulmonary fibrosis mouse model. We demonstrate that in the context of chitinase induction and the macrophage-specific expression of CHIT1, this model recapitulates lung fibrosis in ILDs. Genetic inactivation of Chit1 attenuated bleomycin-induced fibrosis (decreasing the Ashcroft scoring by 28%) and decreased expression of profibrotic factors in lung tissues. Pharmacological inhibition of chitinases by OATD-01 reduced fibrosis and soluble collagen concentration. OATD-01 exhibited anti-fibrotic activity comparable to pirfenidone resulting in the reduction of the Ashcroft score by 32% and 31%, respectively. These studies provide a preclinical proof-of-concept for the antifibrotic effects of OATD-01 and establish CHIT1 as a potential new therapeutic target for IPF.

Targeting Oxidative Stress as a Therapeutic Approach for Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by an abnormal reepithelialisation, an excessive tissue remodelling and a progressive fibrosis within the alveolar wall that are not due to infection or cancer. Oxidative stress has been proposed as a key molecular process in pulmonary fibrosis development and different components of the redox system are altered in the cellular actors participating in lung fibrosis. To this respect, several activators of the antioxidant machinery and inhibitors of the oxidant species and pathways have been assayed in preclinical in vitro and in vivo models and in different clinical trials. This review discusses the role of oxidative stress in the development and progression of IPF and its underlying mechanisms as well as the evidence of oxidative stress in human IPF. Finally, we analyze the mechanism of action, the efficacy and the current status of different drugs developed to inhibit the oxidative stress as anti-fibrotic therapy in IPF.

Health Care Costs at the End of Life for Patients with Idiopathic Pulmonary Fibrosis. Evaluation of a Pilot Multidisciplinary Collaborative Interstitial Lung Disease Clinic.

Rationale: Even though idiopathic pulmonary fibrosis (IPF) is a disease with high morbidity and mortality and no cure, palliative care is rarely implemented, leading to high symptom burden and unmet care needs. In 2012, we implemented a multidisciplinary collaborative (MDC) care model linking clinic and community multidisciplinary teams to provide an early integrated palliative approach, focusing on early symptom management and advance care planning.Objectives: To evaluate the differences in resource use and associated costs of end-of-life care between patients with IPF who received early integrated palliative care and patients with IPF who received conventional treatment.Methods: Using administrative health data, we identified all patients in the Province of Alberta, Canada, who presented to a hospital with an IPF diagnosis between January 1, 2012, and December 31, 2018, and died within this time frame. We compared three groups of patients: those who received MDC care (our clinic patients), specialist care (SC; respirologist), or non-specialist care (NSC; no contact with a respiratory clinic). The primary outcomes were healthcare resource use and costs in the year before death.Results: Of 2,768 patients across the three study groups, in the last year of life, MDC patients were more than three times as likely as SC patients to have received antifibrotic therapies (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.8-5.2), almost twice as likely to have received pulmonary rehabilitation (OR, 1.9; 95% CI, 1.1-3.4), and 36% more likely to have received opiates (OR, 1.4; 95% CI, 0.8-2.3). The median total healthcare costs in the last 3 months of life were approximately C$7,700 lower for MDC patients than for those receiving SC, driven primarily by fewer hospitalizations and emergency department visits. MDC patients were also less likely to die in the hospital (44.9% MDC vs. 64.9% SC vs. 66.8% NSC; P < 0.001) and had the highest rates of no hospitalization in the last year of life.Conclusions: An integrated palliative approach in IPF is associated with improvements in the quality of end-of-life care and reduction in costs. Transformation of care models is required to deliver palliative care for patients with IPF. MDC teams within such models can address the high burden of unmet needs for symptom management, advance care planning, and community support in this complex population.

Early integrated palliative approach for idiopathic pulmonary fibrosis: A narrative study of bereaved caregivers’ experiences

Background: Idiopathic pulmonary fibrosis has an uncertain and rapid trajectory after diagnosis. Palliative care is rarely utilized, although both patients and caregivers experience a distressingly high symptom burden. Most patients die in hospital. Aim: The purpose of this study was to explore bereaved caregivers’ experiences and perceptions of an early integrated palliative approach implemented at a Multidisciplinary Interstitial Lung Disease Clinic. Design: A narrative approach was used, with thematic and content analysis of open-ended interviews. Setting/participants: The clinic is located in a large western Canadian city. Caregivers of deceased patients were recruited through purposive sampling. The eight participants were either spouses or adult children. Results: Five major themes were identified: Having a Terminal Disease; Planning Goals and Wishes for Care; Living Life and Creating Memories; Feeling Strain and Responsibility; and Nearing the End. Caregivers had little understanding of prognosis prior to advance care planning conversations at the clinic. Advance care planning conversations enabled caregivers to know and support patients’ goals and wishes. Caregivers described feeling informed, prepared, and supported when death was near. They expressed neither distress nor anxiety related to patients’ symptoms or strain of relationships. Conclusion: Collaboration and close communication among caregivers, respirologists, and home care enabled effective symptom management and out of hospital deaths. Patients and caregivers had opportunities to enjoy events, create memories, determine preferences, and make plans. Further research on an early integrated palliative approach in Idiopathic Pulmonary Fibrosis is warranted related to quality of life, experience with death and dying, and caregiver bereavement.

Single Versus Double Lung Transplantation in Pulmonary Fibrosis: A Debated Topic

Idiopathic pulmonary fibrosis (IPF) represents the second most frequent indication for lung transplantation after chronic obstructive pulmonary disease. Survival rate after transplantation is poorer compared with other lung diseases for reasons that are not completely clear. Medical therapy with anti-inflammatory drugs may improve symptoms and quality of life, but it does not influence the survival rate. Lung transplantation is the best therapy for end-stage IPF. The debate regarding the superiority of double lung transplantation (DLT) compared with single lung transplantation (SLT) is still ongoing. Until some years ago, SLT was almost uniformly utilized for this indication. In the most recent years, a larger application of DLT has been observed worldwide, probably related to higher 1-year and 5-year survivals. The unanswered question is whether it is ethical to use two lungs for the same patient, considering the donor shortage, when a single lung would suffice. Many reports have demonstrated that SLT offers acceptable pulmonary function and satisfactory early and intermediate survival. Probably DLT should be reserved for younger recipients, for those with concomitant or possible chronic infection of the contralateral lung, or cases of marginal donors. Further studies will be needed to formulate recommendations regarding the preferred surgical approach in IPF.