Int J Mol Sci. 2021 Jun 5;22(11):6107. doi: 10.3390/ijms22116107.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. During the past decade, novel pathogenic mechanisms of IPF have been elucidated that have shifted the concept of IPF from an inflammatory-driven to an epithelial-driven disease. Dysregulated repair responses induced by recurrent epithelial cell damage and excessive extracellular matrix accumulation result in pulmonary fibrosis. Although there is currently no curative therapy for IPF, two medications, pirfenidone and nintedanib, have been introduced based on understanding the pathogenesis of the disease. In this review, we discuss advances in understanding IPF pathogenesis, highlighting epithelial-mesenchymal transition (EMT), the ubiquitin-proteasome system, and endothelial cells. TGF-β is a central regulator involved in EMT and pulmonary fibrosis. HECT-, RING finger-, and U-box-type E3 ubiquitin ligases regulate TGF-β-Smad pathway-mediated EMT via the ubiquitin-proteasome pathway. p27 degradation mediated by the SCF-type E3 ligase, Skp2, contributes to the progression of pulmonary fibrosis by promotion of either mesenchymal fibroblast proliferation, EMT, or both. In addition to fibroblasts as key effector cells in myofibroblast differentiation and extracellular matrix deposition, endothelial cells also play a role in the processes of IPF. Endothelial cells can transform into myofibroblasts; therefore, endothelial-mesenchymal transition can be another source of myofibroblasts.

PMID:34198949 | DOI:10.3390/ijms22116107

ERJ Open Res. 2021 Jun 28;7(2):00818-2020. doi: 10.1183/23120541.00818-2020. eCollection 2021 Apr.

ABSTRACT

Chronic breathlessness occurs across many different conditions, often independently of disease severity. Yet, despite being strongly linked to adverse outcomes, the consideration of chronic breathlessness as a stand-alone therapeutic target remains limited. Here we use data-driven techniques to identify and confirm the stability of underlying features (factors) driving breathlessness across different cardiorespiratory diseases. Questionnaire data on 182 participants with main diagnoses of asthma (21.4%), COPD (24.7%), heart failure (19.2%), idiopathic pulmonary fibrosis (18.7%), other interstitial lung disease (2.7%), and "other diagnoses" (13.2%) were entered into an exploratory factor analysis (EFA). Participants were stratified based on their EFA factor scores. We then examined model stability using 6-month follow-up data and established the most compact set of measures describing the breathlessness experience. In this dataset, we have identified four stable factors that underlie the experience of breathlessness. These factors were assigned the following descriptive labels: 1) body burden, 2) affect/mood, 3) breathing burden and 4) anger/frustration. Stratifying patients by their scores across the four factors revealed two groups corresponding to high and low burden. These two groups were not related to the primary disease diagnosis and remained stable after 6 months. In this work, we identified and confirmed the stability of underlying features of breathlessness. Previous work in this domain has been largely limited to single-diagnosis patient groups without subsequent re-testing of model stability. This work provides further evidence supporting disease independent approaches to assess breathlessness.

PMID:34195256 | PMC:PMC8236755 | DOI:10.1183/23120541.00818-2020

ERJ Open Res. 2021 Jun 28;7(2):00037-2021. doi: 10.1183/23120541.00037-2021. eCollection 2021 Apr.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic fibrosis, and acute exacerbation of IPF (AE-IPF) is the leading cause of death in patients with IPF. Data on the association between the body mass index (BMI) and prognosis of AE-IPF are lacking. This study was performed to evaluate the association between BMI and in-hospital mortality in patients who developed AE-IPF using a national inpatient database.

METHODS: Using the Japanese Diagnosis Procedure Combination database, we retrospectively collected data of inpatients with AE-IPF from 1 July, 2010 to 31 March, 2018. We performed a multivariable logistic regression analysis to evaluate the association between all-cause in-hospital mortality and BMI, categorised as underweight (<18.5 kg·m-2), low-normal weight (18.5-22.9 kg·m-2), high-normal weight (23.0-24.9 kg·m-2), overweight (25.0-29.9 kg·m-2) and obese (≥30.0 kg·m-2).

RESULTS: In total, 14 783 patients were eligible for this study. The in-hospital mortality rate was 59.0%, 55.0%, 53.8%, 54.8% and 46.0% in the underweight, low-normal weight, high-normal weight, overweight and obese groups, respectively. Underweight patients had a significantly higher mortality rate (OR 1.25, 95% CI 1.10-1.42) and obese patients had a significantly lower mortality rate (OR 0.71, 95% CI 0.54-0.94) than low-normal weight patients.

CONCLUSION: Among patients with AE-IPF, the underweight group had higher mortality and the obese group had lower mortality.

PMID:34195254 | PMC:PMC8236619 | DOI:10.1183/23120541.00037-2021

ERJ Open Res. 2021 Jun 28;7(2):00773-2020. doi: 10.1183/23120541.00773-2020. eCollection 2021 Apr.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) has a dismal prognosis. Mesenchymal stromal cells (MSCs) have shown benefit in other inflammatory diseases.

OBJECTIVES: To evaluate the safety and feasibility of endobronchial administration of bone marrow autologous MSCs (BM-MSC) in patients with mild-to-moderate IPF.

METHODS: A phase I multicentre clinical trial (ClinicalTrials.gov NCT01919827) with a single endobronchial administration of autologous adult BM-MSCs in patients diagnosed with mild-to-moderate IPF. In a first escalating-dose phase, three patients were included sequentially in three dose cohorts (10×106, 50×106 and 100×106 cells). In a second phase, nine patients received the highest tolerated dose. Follow-up with pulmonary function testing, 6-min walk test and St George's Respiratory Questionnaire was done at 1, 2, 3, 6 and 12 months, and with computed tomography at 3, 6 and 12 months.

RESULTS: 21 bone marrow samples were obtained from 17 patients. Three patients were excluded from treatment due to chromosome aberrations detected in MSCs after culture, and one patient died before treatment. Finally, 13 patients received the BM-MSC infusion. No treatment-related severe adverse events were observed during follow-up. Compared to baseline, the mean forced vital capacity showed an initial decline of 8.1% at 3 months. The number of patients without functional progression was six (46%) at 3 months and three (23%) at 12 months.

CONCLUSIONS: The endobronchial infusion of BM-MSCs did not cause immediate serious adverse events in IPF patients, but a relevant proportion of patients suffered clinical and/or functional progression. Genomic instability of BM-MSCs during culture found in three patients may be troublesome for the use of autologous MSCs in IPF patients.

PMID:34195252 | PMC:PMC8236617 | DOI:10.1183/23120541.00773-2020

Front Immunol. 2021 Jun 14;12:629854. doi: 10.3389/fimmu.2021.629854. eCollection 2021.

ABSTRACT

BACKGROUND: There is growing evidence found that the role of hypoxia and immune status in idiopathic pulmonary fibrosis (IPF). However, there are few studies about the role of hypoxia and immune status in the lung milieu in the prognosis of IPF. This study aimed to develop a hypoxia-immune-related prediction model for the prognosis of IPF.

METHODS: Hypoxia and immune status were estimated with microarray data of a discovery cohort from the GEO database using UMAP and ESTIMATE algorithms respectively. The Cox regression model with the LASSO method was used for identifying prognostic genes and developing hypoxia-immune-related genes. Cibersort was used to evaluate the difference of 22 kinds of immune cell infiltration. Three independent validation cohorts from GEO database were used for external validation. Peripheral blood mononuclear cell (PBMC) and bronchoalveolar lavage fluid (BALF) were collected to be tested by Quantitative reverse transcriptase-PCR (qRT-PCR) and flow cytometry from 22 clinical samples, including 13 healthy controls, six patients with non-fibrotic pneumonia and three patients with pulmonary fibrosis.

RESULTS: Hypoxia and immune status were significantly associated with the prognosis of IPF patients. High hypoxia and high immune status were identified as risk factors for overall survival. CD8+ T cell, activated CD4+ memory T cell, NK cell, activated mast cell, M1 and M0 macrophages were identified as key immune cells in hypoxia-immune-related microenvironment. A prediction model for IPF prognosis was established based on the hypoxia-immune-related one protective and nine risk DEGs. In the independent validation cohorts, the prognostic prediction model performed the significant applicability in peripheral whole blood, peripheral blood mononuclear cell, and lung tissue of IPF patients. The preliminary clinical specimen validation suggested the reliability of most conclusions.

CONCLUSIONS: The hypoxia-immune-based prediction model for the prognosis of IPF provides a new idea for prognosis and treatment.

PMID:34194423 | PMC:PMC8236709 | DOI:10.3389/fimmu.2021.629854

Medicine (Baltimore). 2021 Jul 2;100(26):e26449. doi: 10.1097/MD.0000000000026449.

ABSTRACT

RATIONALE: Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression.

PATIENT CONCERNS: A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs.

DIAGNOSES: Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP.

INTERVENTIONS: Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary.

OUTCOMES: CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient.

LESSONS: OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.

PMID:34190169 | DOI:10.1097/MD.0000000000026449

Compr Physiol. 2021 Jun 30;11(3):2227-2247. doi: 10.1002/cphy.c200027.

ABSTRACT

Pericytes are mesenchymal-derived mural cells localized within the basement membrane of pulmonary and systemic capillaries. Besides structural support, pericytes control vascular tone, produce extracellular matrix components, and cytokines responsible for promoting vascular homeostasis and angiogenesis. However, pericytes can also contribute to vascular pathology through the production of pro-inflammatory and pro-fibrotic cytokines, differentiation into myofibroblast-like cells, destruction of the extracellular matrix, and dissociation from the vessel wall. In the lung, pericytes are responsible for maintaining the integrity of the alveolar-capillary membrane and coordinating vascular repair in response to injury. Loss of pericyte communication with alveolar capillaries and a switch to a pro-inflammatory/pro-fibrotic phenotype are common features of lung disorders associated with vascular remodeling, inflammation, and fibrosis. In this article, we will address how to differentiate pericytes from other cells, discuss the molecular mechanisms that regulate the interactions of pericytes and endothelial cells in the pulmonary circulation, and the experimental tools currently used to study pericyte biology both in vivo and in vitro. We will also discuss evidence that links pericytes to the pathogenesis of clinically relevant lung disorders such as pulmonary hypertension, idiopathic lung fibrosis, sepsis, and SARS-COVID. Future studies dissecting the complex interactions of pericytes with other pulmonary cell populations will likely reveal critical insights into the origin of pulmonary diseases and offer opportunities to develop novel therapeutics to treat patients afflicted with these devastating disorders. © 2021 American Physiological Society. Compr Physiol 11:2227-2247, 2021.

PMID:34190345 | DOI:10.1002/cphy.c200027

Int J Chron Obstruct Pulmon Dis. 2021 Jun 21;16:1873-1885. doi: 10.2147/COPD.S307192. eCollection 2021.

ABSTRACT

BACKGROUND: Disease heterogeneity in idiopathic pulmonary fibrosis (IPF) often complicates the systematic study of disease, management of patients and clinical investigations.

OBJECTIVE: To describe combined pulmonary fibrosis emphysema (CPFE) phenotype in a rural Appalachian IPF cohort with the highest smoking rates in the United States.

METHODS: CPFE patients (n = 60) in a developed IPF cohort (n = 153) were characterized. Groups (CPFE vs IPF without emphysema) were categorized based on the predominant HRCT patterns of UIP (n = 109). Demographics, clinical variables, and treatment details were recorded. Kaplan-Meier survival and multivariate logistic regression analysis were performed.

RESULTS: The prevalence of CPFE in our IPF cohort was 45% (n = 49). The CPFE group was younger (73.9 vs 78.2), had a more extensive smoking history (93.9% vs 53.3%) with greater mean smoking pack years (49.09 vs 15.39) and had lower percentage predicted DLCO on presentation (38.35 vs 51.09) compared to IPF without emphysema group. Both groups shared equivalent higher burden of comorbidities, including pulmonary hypertension (PH) (46.9% vs 33.3%). One-fifth of patients were prescribed antifibrotics and only a subset (5%) of patients underwent lung transplantation. There was a non-significant trend towards reduced survival in CPFE (p = 0.076). Smoking status and DLCO predicted CPFE in our cohort. Body mass index (BMI), PH, and pirfenidone use were significant predictors of mortality.

CONCLUSION: CPFE was highly prevalent in our rural IPF cohort. In contrast to previous studies, CPFE group was older and had higher female (approx. 30%) occurrence. A greater exposure to cigarette smoke and reduced DLCO at diagnosis predicted CPFE. Lower BMI and PH predicted higher mortality whereas use of pirfenidone improved survival in our cohort. This study highlights a complex interaction of cigarette smoking, advanced fibrosis of UIP, PH and potential utility of antifibrotic agents in CPFE phenotype. Substantial burden of comorbidities, older age, and the limited utilization of advanced therapeutics in the cohort emphasize the challenges faced by rural Appalachian patients.

PMID:34188464 | PMC:PMC8232869 | DOI:10.2147/COPD.S307192

BMJ Open. 2021 Jun 29;11(6):e047249. doi: 10.1136/bmjopen-2020-047249.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown aetiology with a poor prognosis. Several clinical trials of nintedanib in patients with IPF have reported its inhibitory effect on reduced lung function, incidence of acute exacerbation of IPF and worsened health-related quality of life. Although nintedanib has a manageable safety and tolerability profile over long-term use, it was discontinued in over 20% of patients because of adverse events such as diarrhoea and liver dysfunction. This might explain why nintedanib use in patients with IPF is not widespread, especially among patients with early-stage IPF. In the present study, we aimed to clarify the efficacy, safety and tolerability of nintedanib in patients with stage I/II IPF, based on the Japanese IPF disease severity staging classification system.

METHODS AND ANALYSIS: This is an ongoing, prospective, multicentre observational cohort study of patients with stage I/II IPF who will start receiving nintedanib. Totally, 215 patients at 35 sites in Kyushu and Okinawa, Japan will be enrolled and followed up for 3 years. Nintedanib therapy would be initiated at the discretion of the investigator. The primary endpoint, change in forced vital capacity (FVC) at 156 weeks, will be shown as the mean change in FVC from baseline to week 156 with 95% CIs estimated using the Wald method. The safety endpoint-occurrence of adverse events-will be assessed in each system organ class/preferred term.

ETHICS AND DISSEMINATION: The study protocol and informed consent documents were approved by the Institutional Review Board at Nagasaki University Hospital (approval number 19102146) and each participating site. Written informed consent was obtained from all participants. Patient recruitment has begun. The results will be disseminated through scientific peer-reviewed publications and national and international conferences.

TRIAL REGISTRATION NUMBER: UMIN000038192.

PMID:34187824 | DOI:10.1136/bmjopen-2020-047249

Chest. 2021 Jun 26:S0012-3692(21)01265-4. doi: 10.1016/j.chest.2021.06.037. Online ahead of print.

ABSTRACT

Pulmonary fibrosis comprises a wide range of fibrotic lung diseases with unknown pathogenesis and poor prognosis. Familial pulmonary fibrosis (FPF) represents a unique subgroup of patients in which at least one other relative is also affected. Patients with FPF exhibit a wide range of pulmonary fibrosis phenotypes, although idiopathic pulmonary fibrosis is the most common subtype. Despite variable disease manifestations, FPF patients experience worse survival compared to their sporadic counterparts. Therefore, ascertaining a positive family history not only provides prognostic value, but should also raise suspicion for the inheritance of an underlying causative genetic variant within kindreds. By focusing on FPF kindreds, rare variants within surfactant metabolism and telomere maintenance genes have been discovered. However, such genetic variation is not solely restricted to FPF as similar rare variants are found in seemingly sporadic pulmonary fibrosis patients, further supporting the idea of genetic susceptibility underlying pulmonary fibrosis as a whole. Researchers are beginning to demonstrate how the presence of rare variants may inform clinical management, such as informing predisposition risk for yet unaffected relatives as well as informing prognosis and therapeutic strategy for those already affected. Despite these advances, rare variants in surfactant and telomere related genes only explain the genetic basis in about one-quarter of FPF kindred. Therefore, research is needed to identify the missing genetic contributors of pulmonary fibrosis which would not only improve our understanding of disease pathobiology but may offer additional opportunities to improve the health of our patients.

PMID:34186035 | DOI:10.1016/j.chest.2021.06.037

Chest. 2021 Jun 26:S0012-3692(21)01264-2. doi: 10.1016/j.chest.2021.06.036. Online ahead of print.

ABSTRACT

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is recognized as a characteristic syndrome of smoking-related interstitial lung disease that has a worse prognosis than idiopathic pulmonary fibrosis (IPF). However, outcomes after lung transplantation for CPFE have not been reported. The aim of this study is to describe the clinical features and outcomes of CPFE after lung transplantation.

RESEARCH QUESTION: What are the clinical features and outcomes of CPFE after lung transplantation?

STUDY DESIGN AND METHODS: This is a single-center retrospective cohort study of patients with CPFE and IPF who underwent lung transplantation at our center between January 2011 and December 2016. We defined CPFE as ≥ 10% emphysema in the upper lung fields combined with fibrosis on high-resolution computed tomography scan. We characterized the clinical features of patients with CPFE and compared their outcomes after lung transplantation to those with IPF.

RESULTS: 27 of 172 (16%) patients with IPF met criteria for CPFE. Severe pulmonary hypertension was present in 16 of 27 (59%) patients with CPFE. On logistic regression analysis, CPFE was significantly associated with primary graft dysfunction (PGD) grade 3 (odds ratio: 3.14, 95% confidence interval [CI]: 1.18-8.37, p=0.02). On competing risk regression analysis, CPFE was associated with acute cellular rejection (ACR) grade ≥ A2, and chronic lung allograft dysfunction (CLAD) (hazard ratio [HR]: 1.89, 95% CI: 1.10-3.25, p=0.02, HR: 1.96, 95% CI: 1.02-3.77, p=0.04, respectively). 5-year survival was 79.0% for the CPFE group and 75.4% for the IPF group, respectively (log rank p = 0.684).

INTERPRETATION: After transplant, patients with CPFE were more likely to develop PGD, ACR, and CLAD compared to those with IPF. However, survival was not significantly different between the 2 groups.

PMID:34186034 | DOI:10.1016/j.chest.2021.06.036

Curr Opin Pulm Med. 2021 Jun 28. doi: 10.1097/MCP.0000000000000802. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: The term interstitial pneumonia with autoimmune features (IPAF) was first proposed by an international task force in 2015 as a research classification to standardise nomenclature regarding patients with idiopathic interstitial pneumonia and features of connective tissue disease. However, how the use of this term and its proposed definition translates to clinical practice remains uncertain. This review will provide a comprehensive overview of studies of IPAF cohorts to date, discuss the consideration of IPAF as a distinct diagnostic entity and outline a suggested approach to patient management.

RECENT FINDINGS: Considerable heterogeneity exists between published IPAF cohorts, with some cohorts exhibiting similarities to those with connective tissue disease-associated interstitial lung disease (CTD-ILD), and others more similar to idiopathic interstitial pneumonias including idiopathic pulmonary fibrosis (IPF). Little data exist to inform the management of patients who fulfil the IPAF criteria. Preliminary data supports pragmatic management of these patients as having a working clinical diagnosis of either idiopathic interstitial pneumonia or CTD-ILD. Future research studies into this approach are required.

SUMMARY: The term IPAF, and its definition, have been of fundamental benefit to facilitating research in this diverse patient group. However, to date, there remain many unanswered questions regarding their natural histories and response to treatment.

PMID:34183525 | DOI:10.1097/MCP.0000000000000802

Eur J Med Res. 2021 Jun 27;26(1):62. doi: 10.1186/s40001-021-00522-w.

ABSTRACT

BACKGROUND: Differential diagnosis of interstitial lung diseases (ILDs) during the COVID-19 pandemic is difficult, due to similarities in clinical and radiological presentation between COVID-19 and other ILDs on the one hand, and frequent false-negative swab results on the other. We describe a rare form of interstitial and organizing pneumonia resembling COVID-19, emphasizing some key aspects to focus on to get the right diagnosis and treat the patient properly.

CASE PRESENTATION: A 76-year-old man presented with short breath and dry cough in the midst of the COVID-19 outbreak. He showed bilateral crackles and interstitial-alveolar opacities on X-ray, corresponding on computed tomography (CT) to extensive consolidations with air bronchograms, surrounded by ground glass opacities (GGO). Although his throat-and-nasopharyngeal swab tested negative, the picture was overall compatible with COVID-19. On the other hand, he showed subacute, rather than hyperacute, clinical onset; few and stable parenchymal consolidations, rather than patchy and rapidly evolving GGO; pleural and pericardial thickening, pleural effusion, and lymph node enlargement, usually absent in COVID-19; and peripheral eosinophilia, rather than lymphopenia, suggestive of hypersensitivity. In the past year, he had been taking amiodarone for a history of ventricular ectopic beats. CT scans, in fact, highlighted hyperattenuation areas suggestive of amiodarone pulmonary accumulation and toxicity. Bronchoalveolar lavage fluid (BALF) investigation confirmed the absence of coronavirus genome in the lower respiratory tract; conversely, high numbers of foamy macrophages, eosinophils, and cytotoxic T lymphocytes with low CD4/CD8 T-cell ratio were detected, confirming the hypothesis of amiodarone-induced cryptogenic organizing pneumonia. Timely discontinuation of amiodarone and initiation of steroid therapy led to resolution of respiratory symptoms, systemic inflammation, and radiographic opacities.

CONCLUSIONS: A comprehensive analysis of medical and pharmacological history, clinical onset, radiologic details, and peripheral and BALF cellularity, is required for a correct differential diagnosis and management of ILDs in the COVID-19 era.

PMID:34176493 | PMC:PMC8236223 | DOI:10.1186/s40001-021-00522-w

Minerva Med. 2021 Jun 28. doi: 10.23736/S0026-4806.20.07225-0. Online ahead of print.

ABSTRACT

AIM: The aim of this study was the evaluation of the combination of Pycnogenol® (150 mg/day) and Centella asiatica (Centellicum® 3 x 225 mg/day) (PY-CE) for 8 months in subjects with sequelae of idiopathic interstitial pneumonia (IIP). Recently, post-COVID-19 lung disease is emerging with large numbers of patients left with chronic lung conditions. Considering the antifibrotic activity of the combination PY-CE, we also tested this supplementary management in post-COVID-19 lung patients.

RESULTS: 19 subjects with idiopathic interstitial pneumonia (IIP) were included in the study. High Resolution CT scans at inclusion confirmed the presence of lung fibrosis: 10 patients were treated with the Pycnogenol® Centellicum® combination and 9 subjects with standard management (SM) served as controls. Oxidative stress that was very high in all subjects at inclusion, decreased significantly in the supplement group (p<0.05). The Karnofsky performance scale index significantly improved in the supplement group in comparison with controls (p<0.05). The symptoms (fatigue, muscular pain, dyspnea) were significantly lower after 8 months in supplemented patients (p<0.05) as compared with controls. At the end of the study, the small cystic lesions (honeycombing) and traction bronchiectasis were stable or in partial regression in 4 subjects in the supplemented group (vs none in the control group) with a significant improvement in tissue edema in the supplemented subjects. On ultrasound lung scans the white (more echogenic) fibrotic component at inclusion was 18.5±2.2% in the images in controls vs 19.4±2.7% in the supplement group. At the end of the study, there was no improvement in controls (18.9±2.5%) vs a significant improvement in supplemented subjects (16.2±2.1%; p<0.05). In addition, 18 subjects with post-COVID-19 lung disease were included in the study; 10 patients were treated with the Pycnogenol® Centellicum® combination and evaluated after 4 weeks; 8 patients served as controls. Preliminary results show that symptoms associated with post-COVID-19 lung disease after 4 weeks were significantly improved with the supplement combination (p<0.05). Oxidative stress and the Karnofsky performance scale index scale were significantly improved in the supplements group as compared with controls (p<0.05).

CONCLUSIONS: According to these observations, Pycnogenol® controls and decreases edema in several conditions and Centellicum® - modulating the apposition of collagen - modulates the development of irregular cicatrization, keloidal scarring and fibrosis. More time is needed to evaluate this effect in a larger number of post-COVID-19 patients with lung disease. This disease has affected millions of subjects worldwide, leaving severe consequences. Pycnogenol® and Centellicum® may improve the residual clinical picture in post-COVID-19 lung disease (PCL) patients and may reduce the number of subjects evolving into lung fibrosis. The evolution from edema to fibrosis seems to be slower or attenuated with this supplement combination both in Idiopathic pulmonary fibrosis (IPF) and in PCL patients.

PMID:34180638 | DOI:10.23736/S0026-4806.20.07225-0

Cureus. 2021 May 23;13(5):e15200. doi: 10.7759/cureus.15200.

ABSTRACT

Many classes of drugs are known to cause a photosensitive reaction, including anti-bacterial, anti-inflammatory, and nonsteroidal drugs. Pirfenidone is an anti-inflammatory drug that is used to treat idiopathic pulmonary fibrosis (IPF). We report a case of a patient who developed a photosensitive rash secondary to pirfenidone use, which resolved after discontinuing administration of the drug.

PMID:34178520 | PMC:PMC8219430 | DOI:10.7759/cureus.15200

J Comput Assist Tomogr. 2021 Jun 26. doi: 10.1097/RCT.0000000000001182. Online ahead of print.

ABSTRACT

OBJECTIVE: Several software-based quantitative computed tomography (CT) analysis methods have been developed for assessing emphysema and interstitial lung disease. Although the texture classification method appeared to be more successful than the other methods, the software programs are not commercially available, to our knowledge. Therefore, this study aimed to investigate the usefulness of a commercially available software program for quantitative CT analyses.

METHODS: This prospective cohort study included 80 patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF).

RESULTS: The percentage of low attenuation volume and high attenuation volume had high sensitivity and high specificity for detecting emphysema and pulmonary fibrosis, respectively. The percentage of diseased lung volume (DLV%) was significantly correlated with the lung diffusion capacity for carbon monoxide in all patients with COPD and IPF patients.

CONCLUSIONS: The quantitative CT analysis may improve the precision of the assessment of DLV%, which itself could be a useful tool in predicting lung diffusion capacity in patients with the clinical diagnosis of COPD or IPF.

PMID:34176875 | DOI:10.1097/RCT.0000000000001182

Respir Investig. 2021 Jun 24:S2212-5345(21)00107-6. doi: 10.1016/j.resinv.2021.05.012. Online ahead of print.

ABSTRACT

Fibrosis is characterized by the deposition of extracellular matrix (ECM) proteins, while idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by dysregulated tissue repair and remodeling. Anti-inflammatory drugs, such as corticosteroids and immunosuppressants, and antifibrotic drugs, like pirfenidone and nintedanib, are used in IPF therapy. However, their limited effects suggest that single mediators are inadequate to control IPF. Therefore, therapies targeting the multifactorial cascades that regulate tissue remodeling in fibrosis could provide alternate solutions. ECM molecules have been shown to modulate various biological functions beyond tissue structure support and thus, could be developed into novel therapeutic targets for modulating tissue remodeling. Among ECM molecules, glycosaminoglycans (GAG) are linear polysaccharides consisting of repeated disaccharides, which regulate cell-matrix interactions. Chondroitin sulfate (CS), one of the major GAGs, binds to multifactorial mediators in the ECM and reportedly participates in tissue remodeling in various diseases; however, to date, its biological functions have drawn considerably less attention than other GAGs, like heparan sulfate. In the present review, we discuss the involvement and regulation of CS in tissue remodeling and pulmonary fibrotic diseases, its role in pulmonary fibrosis, and the therapeutic approaches targeting CS.

PMID:34176780 | DOI:10.1016/j.resinv.2021.05.012

Eur Respir J. 2021 Jun 25:2003979. doi: 10.1183/13993003.03979-2020. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments we used genetic determinants of circulating proteins which reside cis to the encoded gene (cis-SNPs), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalization analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.MR analyses of 834 proteins found that a one sd increase in circulating FUT3 and FUT5 was associated with a reduced risk of IPF (OR: 0.81, 95%CI: 0.74-0.88, p=6.3×10-7, and OR: 0.76, 95%CI: 0.68-0.86, p=1.1×10-5). Sensitivity analyses including multiple-cis SNPs provided similar estimates both for FUT3 (inverse variance weighted [IVW] OR: 0.84, 95%CI: 0.78-0.91, p=9.8×10-6, MR-Egger OR: 0.69, 95%CI: 0.50-0.97, p=0.03) and FUT5 (IVW OR: 0.84, 95%CI: 0.77-0.92, p=1.4×10-4, MR-Egger OR: 0.59, 95%CI: 0.38-0.90, p=0.01) FUT3 and FUT5 signals colocalized with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%. Further transcriptomic investigations supported the protective effects of FUT3 for IPF.An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.

PMID:34172473 | DOI:10.1183/13993003.03979-2020

Chest. 2021 Jun 22:S0012-3692(21)01159-4. doi: 10.1016/j.chest.2021.05.071. Online ahead of print.

ABSTRACT

In many studies, more than half of patients with idiopathic pulmonary fibrosis (IPF) endorse cough. In IPF (as in other conditions), when chronic, cough may be frustrating and lead to significant impairments in quality of life. In patients with IPF, comorbid conditions such as gastroesophageal reflux can cause or contribute to cough; when stemming from IPF itself, chronic cough likely arises from multiple mechanisms including mechanical and neurosensory changes. In this article, we review our approach at attempting to identify causes of chronic cough in patients with IPF; these include gastroesophageal reflux disease or upper airway cough syndrome and IPF itself. We cursorily summarize the current evidence for the treatment of chronic cough in IPF, briefly review data on the treatment of unexplained chronic cough and extrapolate it to the treatment of refractory cough in IPF, but we focus our attention on our approaches to evaluation and management, recognizing some may not be supported by a robust cache of data.

PMID:34171385 | DOI:10.1016/j.chest.2021.05.071

Front Pharmacol. 2021 Jun 8;12:675907. doi: 10.3389/fphar.2021.675907. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pulmonary disease characterized with radiographically evident pulmonary infiltrates and extracellular matrix deposition with limited treatment options. We previously described that microcystin-LR (MC-LR) reduces transforming growth factor (TGF)-β1/Smad signaling and ameliorates pulmonary fibrosis in bleomycin (BLM)-induced rat models. In the present study, we further demonstrate that microcystin-RR (MC-RR), an MC congener with lower toxicity than MC-LR, exerted an anti-fibrotic effect on BLM-induced pulmonary fibrosis rodent models and compared it with MC-LR. Our data show that MC-RR treatment attenuated BLM-associated pulmonary inflammation and collagen deposition in both therapeutic and preventive models. MC-RR reduced the expression of fibrotic markers, including vimentin, α-smooth muscle actin, collagen 1α1, and fibronectin, in rat pulmonary tissues. Furthermore, the core features of BLM-induced pulmonary fibrotic lesions were better alleviated by MC-RR than by MC-LR. MC-RR treatment substantially decreased the number of pulmonary M2 macrophages. In vitro, MC-RR attenuated the epithelial-mesenchymal transition and fibroblast-myofibroblast transition triggered by M2 macrophages. Therefore, we highlight MC-RR as a promising molecule for developing therapeutic and prophylactic strategies against IPF, a refractory lung disease.

PMID:34168562 | PMC:PMC8217630 | DOI:10.3389/fphar.2021.675907