Transplant Proc. 2021 Jun 9:S0041-1345(21)00311-0. doi: 10.1016/j.transproceed.2021.04.019. Online ahead of print.

ABSTRACT

We present 2 cases of "hybrid lung transplant," which included sequentially implanting a living lobar graft to 1 side and a cadaveric graft to the other side. This procedure was approved by the institutional review board at Okayama University Hospital. The 2 recipients were diagnosed with severe idiopathic pulmonary fibrosis, and living donor lobar lung transplant was considered; however, 2 appropriate donors were not available. Therefore, we accepted extended criteria donor lungs with a partial pressure of oxygen/fraction of inspired oxygen ratio of <251 mm Hg. However, 1 of the 2 patients developed grade 2 primary graft dysfunction. The living donor lobar lung had a low volume but was in good condition, which contributed to the patient's recovery after primary graft dysfunction during the perioperative period. The other patient's status of bronchiolitis obliterans syndrome had gradually progressed to grade 3, and only the living donor lung was functioning at that time. However, both patients are alive 5.5 and 4.2 years after lung transplant, respectively. Hybrid lung transplantation may increase patients' chances of receiving transplants because patients are not likely to survive while waiting for ideal donor lungs to become available.

PMID:34119337 | DOI:10.1016/j.transproceed.2021.04.019

Int Immunopharmacol. 2021 Jun 9;98:107780. doi: 10.1016/j.intimp.2021.107780. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible inflammatory disease with a high mortality rate and limited therapeutic options. This study explored the potential role and mechanisms of Dehydrocostus lactone (DHL) in the inflammatory and fibrotic responses in a bleomycin (BLM) induced model. Treatment with DHL significantly reduced pathological injury and fibrosis, the secretion of BLM-induced pro-fibrotic mediators TGF-β and α-SMA, and components of the extracellular matrix (fibronectin). Additionally, in the early stages of inflammation, DHL administration inhibited the infiltration of inflammatory cells and downregulated the expression of TGF-β, TNF-α, and IL-6, indicating that DHL treatment effectively alleviated BLM-induced pulmonary fibrosis and inflammation in a dose-dependent manner. Furthermore, BLM induced the production of IL-33 in vivo, which initiated and progressed pulmonary fibrosis by activating macrophages and enhancing the production of IL-13 and TGF-β. In contrast, a significant decrease in the expression of IL-33 after DHL treatment in vitro showed that DHL strongly reduced IL-13 and TGF-β. Regarding the mechanism, BLM-induced phosphorylation of JNK, p38 MAPK, and NF-κB were significantly reduced after DHL treatment, which further led to the down-regulation of IL-33 expression, thereby decreasing IL-13 and TGF-β. Collectively, our data suggested that DHL could exert its anti-fibrosis effect via inhibiting the early inflammatory response by downregulating the JNK/p38 MAPK-mediated NF-κB signaling pathway to suppress macrophage activation. Therefore, DHL has therapeutic potential for pulmonary fibrosis.

PMID:34118645 | DOI:10.1016/j.intimp.2021.107780

Adv Ther. 2021 Jun 11. doi: 10.1007/s12325-021-01790-y. Online ahead of print.

ABSTRACT

INTRODUCTION: Disease behaviour may guide diagnosis and treatment decisions in patients with interstitial lung disease (ILD). STARLINER aimed to characterise disease behaviour in patients with suspected ILD during the peri-diagnostic period using real-time home-based assessments.

METHODS: STARLINER (NCT03261037) was an international, multicentre study. Patients ≥ 50 years old with suspected ILD were followed throughout the peri-diagnostic period, consisting of a pre-diagnostic period (from enrolment to diagnosis) and a post-diagnostic period (from diagnosis to treatment initiation). Study length was variable (≤ 18 months). The primary endpoint was time-adjusted semi-annual forced vital capacity (FVC) change measured during the peri-diagnostic period using daily home spirometry in patients with idiopathic pulmonary fibrosis (IPF). Secondary outcomes included changes in FVC (home spirometry) in patients with non-IPF ILD, changes in FVC (site spirometry), changes in physical functional capacity measured by daily home accelerometry and site 6-min walk distance (6MWD), and changes in patient-reported outcomes (PROs) in IPF or non-IPF ILD.

RESULTS: Of the 178 patients enrolled in the study, 68 patients were diagnosed with IPF, 62 patients were diagnosed with non-IPF ILD, 9 patients received a non-ILD diagnosis and 39 patients did not receive a diagnosis. Technical and analytical issues led to problems in applying the prespecified linear regression model to analyse the home FVC data. Time-adjusted median (quartile [Q]1, Q3) semi-annual FVC change during the peri-diagnostic period measured using home and site spirometry, respectively, was - 147.7 (- 723.8, 376.2) ml and - 149.0 (- 314.6, 163.9) ml for IPF and 19.1 (- 194.9, 519.0) ml and - 23.4 (- 117.9, 133.5) ml in non-IPF ILD. A greater decline in steps per day was observed for IPF versus non-IPF ILD, whereas an increase in 6MWD was observed for patients with IPF versus a decline in 6MWD for patients with non-IPF ILD. No clear patterns of disease behaviour were observed for IPF versus non-IPF ILD for PROs.

CONCLUSIONS: Despite home spirometry being feasible for most patients and centres, technical and analytical challenges in the home-based assessments prevented firm conclusions regarding disease behaviour. This highlights that further optimisation of the technology and analysis methods is required before widespread implementation.

TRIAL REGISTRATION: NCT03261037.

PMID:34117601 | DOI:10.1007/s12325-021-01790-y

J Palliat Med. 2021 Jun 11. doi: 10.1089/jpm.2020.0787. Online ahead of print.

ABSTRACT

Background: The morbidity and mortality of interstitial lung disease (ILD) is high, despite novel therapeutics. Recognizing unmet needs for symptom management, advance care planning (ACP), and support for people with ILD and their families, we developed a palliative care-ILD collaborative care pilot program to improve access to palliative care. Methods: In the quantitative arm of this mixed-methods study, we evaluated which patients were cared for through the palliative care co-management program and the impact of the program on rates of ACP and opioid prescribing. In the qualitative arm, we interviewed patients and family caregivers, as well as pulmonary and palliative care clinicians, to understand perceptions about palliative care. Results: Thirty-one patients were co-managed by the palliative care and ILD teams during the study period. Half (48.4%) had idiopathic pulmonary fibrosis. Mean forced vital capacity (FVC) was 61.7%. Nearly half (48.4%) received all of their palliative care via telehealth. With palliative care, the rate of ACP notes increased from 3.2% to 100% (p < 0.001), rate of advance directive completion increased from 22.6% to 35.5% (p = 0.046), and rate of physician orders for life-sustaining treatments (POLST) form completion increased from 0% to 35.5% (p = 0.001). Half (51.6%) were prescribed opiates, overwhelmingly short-acting opiates to use as needed for severe episodic dyspnea. Themes from the qualitative analyses included that the palliative care team was supportive and patient-centered, improved symptoms and medication side effects, and enhanced illness understanding. Clinicians reported how palliative care co-management improved patient care and clinician experience, but barriers to referral remain including misperceptions about palliative care on the part of providers and patients. Conclusions: Palliative care co-management for patients with moderately severe ILD holds promise, and our experience can inform groups at other centers who are interested in developing such care models. Ongoing challenges include systematically reaching all patients who are likely to benefit.

PMID:34115958 | DOI:10.1089/jpm.2020.0787

Cell Death Dis. 2021 Jun 10;12(6):600. doi: 10.1038/s41419-021-03884-5.

ABSTRACT

Long non-coding RNAs (lncRNAs) have emerged as critical factors for regulating multiple biological processes during organ fibrosis. However, the mechanism of lncRNAs in idiopathic pulmonary fibrosis (IPF) remains incompletely understood. In the present study, two sets of lncRNAs were defined: IPF pathogenic lncRNAs and IPF progression lncRNAs. IPF pathogenic and progression lncRNAs-mRNAs co-expression networks were constructed to identify essential lncRNAs. Network analysis revealed a key lncRNA CTD-2528L19.6, which was up-regulated in early-stage IPF compared to normal lung tissue, and subsequently down-regulated during advanced-stage IPF. CTD-2528L19.6 was indicated to regulate fibroblast activation in IPF progression by mediating the expression of fibrosis related genes LRRC8C, DDIT4, THBS1, S100A8 and TLR7 et al. Further studies showed that silencing of CTD-2528L19.6 increases the expression of Fn1 and Collagen I both at mRNA and protein levels, promoted the transition of fibroblasts into myofibroblasts and accelerated the migration and proliferation of MRC-5 cells. In contrast, CTD-2528L19.6 overexpression alleviated fibroblast activation in MRC-5 cells induced by TGF-β1. LncRNA CTD-2528L19.6 inhibited fibroblast activation through regulating the expression of LRRC8C in vitro assays. Our results suggest that CTD-2528L19.6 may prevent the progression of IPF from early-stage and alleviate fibroblast activation during the advanced-stage of IPF. Thus, exploring the regulatory effect of lncRNA CTD-2528L19.6 may provide new sights for the prevention and treatment of IPF.

PMID:34112765 | DOI:10.1038/s41419-021-03884-5

Eur Respir J. 2021 Jun 10:2100917. doi: 10.1183/13993003.00917-2021. Online ahead of print.

ABSTRACT

RATIONALE: Patients with Idiopathic Pulmonary Fibrosis (IPF) experience impaired health related quality of life (HRQoL). Several tools have been developed to objectively assess HRQoL in this patient population, but none are in use in routine clinical practice.

OBJECTIVES: To develop a rapid, specific tool that can be used for patients with IPF during routine clinic visits.

METHODS: A novel and simple 5-item numerical rating scale (NRS) was developed and compared with two other previously validated tools. 100 consecutive patients with IPF managed at the center for ILD, were recruited to complete the R-Scale-PF, the Kings Brief Interstitial Lung Disease Questionnaire (K-BILD), and the EuroQol 5-Dimensional 5-Level Questionnaire (EQ-5D-5 L) in addition to pulmonary function and 6-min walk tests.

MEASUREMENTS AND MAIN RESULTS: All 100 patients successfully completed the three HRQoL tools with 53 completing them again at follow up visits. Internal consistency was high (Cronbach's α 0.825) with minimal floor/ceiling effect. Concurrent validity of the R-Scale-PF was moderate to high compared with the K-BILD (r=-0.713) and the EQ-5D-5 L (r=-0.665). Concurrent validity was moderate with physiologic measures (forced vital capacity, r=-0.307, 6-min walk distance, r=-0.383). The R-Scale-PF demonstrated good known-groups validity when comparing scores across stages of disease severity.

CONCLUSIONS: The R-Scale-PF correlates well with the K-BILD and EQ-5D-5 L. It is hoped that this novel simple NRS tool subject to validation in patients from other centers will provide the opportunity to objectively measure HRQoL in routine clinical practice for patients with IPF.

PMID:34112729 | DOI:10.1183/13993003.00917-2021

Mol Ther. 2021 Jun 7:S1525-0016(21)00314-2. doi: 10.1016/j.ymthe.2021.06.008. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts origin mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N6-methyladenosine (m6A) modification has been implicated in various biological process. However, the role of m6A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m6A modification is up-regulated in bleomycin induced pulmonary fibrosis mice model, FMT-derived myofibroblasts and idiopathic pulmonary fibrosis patient lung samples. Lowering m6A level through silencing METTL3 inhibits FMT process in vitro and vivo. Mechanistically, KCNH6 is involved in m6A-regulated FMT process. m6A modification regulates the expression of KCNH6 by modulating its translation in a YTHDF1 dependent manner. Together, our study highlights the critical role of m6A modification in pulmonary fibrosis. Manipulation of m6A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis.

PMID:34111558 | DOI:10.1016/j.ymthe.2021.06.008

FEBS J. 2021 Jun 9. doi: 10.1111/febs.16039. Online ahead of print.

ABSTRACT

Fibrosis of visceral organs such as the lungs, heart, kidneys and liver remain a major cause of morbidity and mortality and is also associated with many other disorders, including cancer and metabolic disease. In this review, we focus upon the microfibrillar collagen VI, which is present in the extracellular matrix (ECM) of most tissues. However, expression is elevated in numerous fibrotic conditions, such idiopathic pulmonary disease (IPF), chronic liver and kidney diseases. Collagen VI is composed of three subunits α1, α2 and α3, which can be replaced with alternate chains of α4, α5, or α6. The C-terminal globular domain (C5) of collagen VI α3 can be proteolytically cleaved to form a biologically active fragment termed endotrophin (ETP), which has been shown to actively drive fibrosis, inflammation and insulin resistance. Tissue biopsies have long been considered the gold standard for diagnosis and monitoring of progression of fibrotic disease. The identification of neo-antigens from enzymatically processed collagen chains have revolutionised the biomarker field, allowing rapid diagnosis and evaluation of prognosis of numerous fibrotic conditions, as well as providing valuable clinical trial endpoint determinants. Collagen VI chain fragments such an endotrophin (PRO-C6), C6M and C6Mα3 are emerging as important biomarkers for fibrotic conditions.

PMID:34109754 | DOI:10.1111/febs.16039

ERJ Open Res. 2021 Jun 7;7(2):00733-2020. doi: 10.1183/23120541.00733-2020. eCollection 2021 Apr.

ABSTRACT

ND-L02-s0201 is a lipid nanoparticle encapsulating an siRNA which inhibits expression of heat shock protein 47 (HSP47), a collagen-specific chaperone. Accumulated evidence demonstrates a close association between increased level of HSP47 and excessive accumulation of collagen in fibrotic diseases. Our objective was to test ND-L02-s0201 efficacy in preclinical lung fibrosis models and characterise the downstream histological and functional consequences of inhibiting the expression of HSP47. Comprehensive optimisation and characterisation of bleomycin (BLM) and silica-induced rat lung fibrosis models were conducted, which ensured progressive pathological changes were sustained throughout the study during evaluation of the anti-fibrotic potential of ND-L02-s0201. In the BLM model, we demonstrated dose-dependent and statistically significant reduction in the relative lung weight, collagen deposition and histology, and fibrosis scores following ND-L02-s0201 treatment. Lung tissue mRNA profiling demonstrated that 11 out of 84 fibrosis-relevant genes were upregulated following BLM induction and were downregulated by approximately 4.5-fold following ND-L02-s0201 treatment. Epithelial-mesenchymal transition was characterised in the BLM model following ND-L02-s0201 treatment. Cell enrichment demonstrated that myofibroblasts contained the highest HSP47 mRNA expression. BLM led to more than a five-fold increase in myofibroblasts and ND-L02-s0201 treatment reduced the myofibroblasts to sham levels. Statistically significant improvement in lung function was noted in the BLM model which was determined by running endurance capacity using a 7-minute treadmill test. Comparable anti-fibrotic efficacy was also observed in the silica model. Results from two robust chronic rodent models of pulmonary fibrosis demonstrated significant anti-fibrotic effects and improved lung function which support the evaluation of ND-L02-s0201 in subjects with idiopathic pulmonary fibrosis.

PMID:34109242 | PMC:PMC8181707 | DOI:10.1183/23120541.00733-2020

ERJ Open Res. 2021 Jun 7;7(2):00880-2020. doi: 10.1183/23120541.00880-2020. eCollection 2021 Apr.

ABSTRACT

BACKGROUND: Childhood interstitial and diffuse lung diseases (chILD) encompass a broad spectrum of rare pulmonary disorders. In most developing Middle Eastern countries, chILD is still underdiagnosed. Our objective was to describe and investigate patients diagnosed with chILD in a tertiary university hospital in Egypt.

METHODS: We analysed data of consecutive subjects (aged <18 years) referred for further evaluation at the Children's Hospital, Ain Shams University (Cairo, Egypt). Diagnosis of chILD was made in accordance with the ChILD-EU criteria. The following information was obtained: demographic data, clinical characteristics, chest computed tomography findings, laboratory studies, spirometry, bronchoalveolar lavage and histopathology findings.

RESULTS: 22 subjects were enrolled over 24 months. Median age at diagnosis was 7 years (range 3.5-14 years). The most common manifestations were dyspnoea (100%), cough (90.9%), clubbing (95.5%) and tachypnoea (90.9%). Systematic evaluation led to the following diagnoses: hypersensitivity pneumonitis (n=3), idiopathic interstitial pneumonias (n=4), chILD related to chronic granulomatous disease (n=3), chILD related to small airways disease (n=3), post-infectious chILD (n=2), Langerhans cell histiocytosis (n=2), idiopathic pulmonary haemosiderosis (n=2), granulomatous lymphocytic interstitial lung disease (n=1), systemic sclerosis (n=1) and familial interstitial lung disease (n=1). Among the subjects who completed the diagnostic evaluation (n=19), treatment was changed in 13 (68.4%) subjects.

CONCLUSION: Systematic evaluation and multidisciplinary peer review of chILD patients at our tertiary hospital led to changes in management in 68% of the patients. This study highlights the need for an Egyptian chILD network with genetic testing, as well as the value of collaborating with international groups in improving healthcare for children with chILD.

PMID:34109237 | PMC:PMC8181618 | DOI:10.1183/23120541.00880-2020

Sci Rep. 2021 Jun 9;11(1):12135. doi: 10.1038/s41598-021-91407-9.

ABSTRACT

Circulating monocytes have pathogenic relevance in idiopathic pulmonary fibrosis (IPF). Here, we determined whether the cell surface levels of two markers, pro-inflammatory-related S100A9 and anti-inflammatory-related CD163, expressed on CD14strongCD16- classical monocytes by flow cytometry could discriminate IPF from idiopathic nonspecific interstitial pneumonia (iNSIP). Twenty-five patients with IPF, 25 with iNSIP, and 20 healthy volunteers were prospectively enrolled in this study. The S100A9+CD163- cell percentages in classical monocytes showed a pronounced decrease on monocytes in iNSIP compared to that in IPF. In contrast, the percentages of S100A9-CD163+ cells were significantly higher in iNSIP patients than in IPF patients and healthy volunteers. In IPF patients, there was a trend toward a correlation between the percentage of S100A9+CD163- monocytes and the surfactant protein-D (SP-D) serum levels (r = 0.4158, [95% confidence interval (CI) - 0.02042-0.7191], p = 0.051). The individual percentages of S100A9+CD163- and S100A9-CD163+ cells were also independently associated with IPF through multivariate regression analysis. The unadjusted area under the receiver operating characteristic curve (ROC-AUC) to discriminate IPF from iNSIP was (ROC-AUC 0.802, 95% CI [0.687-0.928]), suggesting that these are better biomarkers than serum SP-D (p < 0.05). This preliminary study reports the first comparative characterization of monocyte phenotypes between IPF and iNSIP.

PMID:34108546 | DOI:10.1038/s41598-021-91407-9

Sci Adv. 2021 Jun 9;7(24):eabg6005. doi: 10.1126/sciadv.abg6005. Print 2021 Jun.

ABSTRACT

Recent studies have identified impaired type 2 alveolar epithelial cell (ATII) renewal in idiopathic pulmonary fibrosis (IPF) human organoids and severe fibrosis when ATII is defective in mice. ATIIs function as progenitor cells and require supportive signals from the surrounding mesenchymal cells. The mechanisms by which mesenchymal cells promote ATII progenitor functions in lung fibrosis are incompletely understood. We identified growth hormone receptor (GHR) is mainly expressed in mesenchymal cells, and its expression is substantially decreased in IPF lungs. Higher levels of GHR expression correlated with better lung function in patients with IPF. Profibrotic mesenchymal cells retarded ATII growth and were associated with suppressed vesicular GHR expression. Vesicles enriched with Ghr promote ATII proliferation and diminished pulmonary fibrosis in mesenchymal Ghr-deficient mice. Our findings demonstrate a previously unidentified mesenchymal paracrine signaling coordinated by GHR that is capable of supporting ATII progenitor cell renewal and limiting the severity of lung fibrosis.

PMID:34108218 | DOI:10.1126/sciadv.abg6005

Mob DNA. 2021 Jun 9;12(1):14. doi: 10.1186/s13100-021-00241-3.

ABSTRACT

BACKGROUND: Transposable elements (TEs) are repetitive sequences of viral origin that compose almost half of the human genome. These elements are tightly controlled within cells, and if activated, they can cause changes in both gene regulation and immune viral responses that have been associated with several chronic inflammatory diseases in humans. As oxidants are potent activators of TEs, and because oxidative injury is a major risk factor in relation to idiopathic pulmonary fibrosis (IPF), we hypothesized that TEs might be involved in the regulation of gene expression and so contribute to inflammation in cases of IPF. IPF is a fatal lung disease that involves the gradual replacement of the alveolar tissue with fibrotic scars as well as the accumulation of inflammatory cells in the lower respiratory tract. Although IPF is known to occur as a result of the complex interaction between age, environmental risk factors (i.e., oxidative stress) and genetics, the relative contributions of these factors to the disease remain unclear. To determine whether TEs are associated with IPF, we compared the transcriptional profiles of the genes and TEs of lung cells obtained from both healthy donors and IPF patients.

RESULTS: We quantified TE and gene expression levels using a published bulk RNA-seq dataset containing 24 subjects (16 donors and eight IPF patients), including three lung-cell types per subject, as well as an scRNA-seq dataset concerning 16 subjects (eight donors and eight IPF patients). We found evidence of TE dysregulation in the alveolar type II lung cells and alveolar macrophages of the IPF patients. In addition, the activation of the LINE1 family of elements in IPF is associated with the increased expression of TE cellular regulators (MOV10, IFI16, SAMHD1, and APOBECG3), interferon-stimulating genes (ISG15, IFI6, IFI27, IFI44, and OAS1), chemokines (CX3CL1 and CXCL9), and interleukins (IL15RA). We also propose that TE derepression might be involved in the regulation of previously reported IPF candidate genes (MUC5B, CHL1, SPP1, and MMP7).

CONCLUSION: Based on our findings, we propose that TE derepression plays an important role in the regulation of gene expression and can also prompt both the recruitment of inflammatory processes and the disruption of the immunological balance, which can lead to chronic inflammation in IPF.

PMID:34108012 | DOI:10.1186/s13100-021-00241-3

Am J Chin Med. 2021 Jun 3:1-22. doi: 10.1142/S0192415X2150052X. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a tumor-like disease, is a serious and fatal pulmonary inflammatory condition usually characterized by irreversible destruction of the lung parenchyma, excessive matrix accumulation, and decline in lung function. IPF still remains a great burden to the universe. At the moment, the available therapeutic regimens utilized for IPF such as non-pharmacological therapies (lung transplantation) and pharmacological therapies (drugs, nintedanib, pirfenidone, etc.) are normally accompanied by significant limitations, such as adverse reactions, low bioavailability, poor selectivity, low-tissue distribution, in vivo instability, systemic toxicity, inconveniency and unsafe usage. There is a need for the exploration and discovery of new novel remedies by researchers and scientists globally. Recent numerous preliminary studies have laid significant emphasis and demonstrated the antifibrotic importance, good curative actions (little or no adverse reactions), and multiple target sites of the active components from traditional herbal medicine (THM) against IPF, which could serve as a modern, alternative and potential therapeutics or drug candidates in treating IPF. This paper extensively summarizes the pharmacological actions and signaling pathways or mechanisms of active components obtained from THM for treating IPF. Moreover, the sources and modernization, markets, relevant FDA and CFDA studies (the USA and China), preclinical analysis, and various compositions of THM currently under clinical trials are also highlighted. Additionally, this present analytical data would be instrumental towards further drug progression or advancement of active components from THM for the potential therapeutics of IPF in the future.

PMID:34107859 | DOI:10.1142/S0192415X2150052X

Am J Respir Cell Mol Biol. 2021 Jun 9. doi: 10.1165/rcmb.2020-0499OC. Online ahead of print.

ABSTRACT

The Wnt/β-catenin pathway initiates a signaling cascade critical in cell differentiation and normal development of multiple organ systems. The reactivation of this pathway has been documented in experimental and human idiopathic pulmonary fibrosis (IPF), wherein Wnt/β-catenin activation has been implicated in epithelial cell repair. Furthermore the canonical ligand Wnt3a is known to induce myofibroblast differentiation, however the role of non-canonical Wnt ligands remains unclear. This study showed significantly higher levels of Wnt11 expression in cells from both IPF patients and bleomycin-treated mice, as well as in TGFβ treated mouse lung fibroblasts. Moreover Wnt11 induced myofibroblast differentiation as manifested by increased α-smooth muscle actin (α-SMA) expression, which was similar to that induced by canonical Wnt3a/β-catenin signaling. Further investigation revealed that Wnt11 induction of α-SMA, was associated with the activation of JNK/c-Jun signaling and inhibited by a JNK inhibitor. The potential importance of this signaling pathway was supported by in vivo evidence showing significantly increased levels of Wnt11 and activated JNK in lungs of mice with bleomycin induced pulmonary fibrosis. Interestingly, fibroblasts did not express canonical Wnt3a but treatment of these cells with exogenous Wnt3a induced endogenous Wnt11 and Wnt5a resulting in repression of the Wnt3a/β-catenin target gene Axin2. These findings suggested that the non-canonical Wnt induction of myofibroblast differentiation mediated by JNK/c-Jun pathway might play a significant role in pulmonary fibrosis, in addition to, or synergy with canonical Wnt3a/β-catenin signaling. Moreover Wnt3a activation of non-canonical Wnt signaling might trigger a switch from canonical to non-canonical Wnt signaling to induce myofibroblast differentiation.

PMID:34107237 | DOI:10.1165/rcmb.2020-0499OC

Turk Gogus Kalp Damar Cerrahisi Derg. 2021 Apr 26;29(2):191-200. doi: 10.5606/tgkdc.dergisi.2021.9490. eCollection 2021 Apr.

ABSTRACT

BACKGROUND: In this study, we aimed to discuss our anesthesia management strategies, experiences, and outcomes in patients undergoing lung transplantation.

METHODS: Between December 2016 and December 2018, a total of 53 patients (43 males, 10 females; mean age: 46.1±13 years; range, 14 to 64 years) undergoing lung transplantation in our center were included. The anesthesia technique, patients" characteristics, and perioperative clinical and follow-up data were recorded. The stage of lung disease was assessed using the New York Heart Association functional classification.

RESULTS: Two patients underwent single lung transplantation, while 51 patients underwent double lung transplantation. Idiopathic pulmonary fibrosis was the most common indication in 41.5% of the patients. All patients had end-stage lung disease (Class IV) and 79% were oxygen-dependent. The extracorporeal membrane oxygenation support was given to 32 patients.

CONCLUSION: The anesthetic management of lung transplantation is challenging, either due to the deterioration of the recipient"s physical performance and the complexity of the surgical techniques used. In general, a kind of mechanical support may be needed and extracorporeal membrane oxygenation is the first choice in the majority of patients. A close communication should be maintained between the surgeons, perfusion technicians, and anesthesiologists to ensure an optimal multidisciplinary approach and to achieve successful outcomes.

PMID:34104513 | PMC:PMC8167475 | DOI:10.5606/tgkdc.dergisi.2021.9490

Respir Res. 2021 Jun 8;22(1):175. doi: 10.1186/s12931-021-01760-6.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse interstitial lung disease, of which the etiology has been poorly understood. Several studies have focused on the relationship between IPF and diabetes mellitus (DM) in the past years but have failed to reach a consensus. This meta-analysis aimed to examine the association between diabetes to IPF.

METHODS: We accumulated studies investigating the association between DM and IPF from databases including Medline, Cochrane Library, Embase, Web of Science, and China National Knowledge Infrastructure. RevMan 5.3 and the Newcastle-Ottawa Scale (NOS) were utilized to analyze the data and assess the quality of the included studies. The value of odds ratio (OR) with 95% confidence interval (CI) was used as the measure to estimate the risk of DM in IPF. Heterogeneity was assessed by I2 statistics. We also performed subgroup analysis, meta-regression, and Egger's test for bias analysis.

RESULTS: Nine case-control studies with 5096 IPF patients and 19,095 control subjects were included in the present meta-analysis, which indicated a positive correlation between DM and IPF (OR 1.65, 95% CI 1.30-2.10; P < 0.0001). Meta-regression and subgroup analysis negated the influence of covariates like cigarette smoking, age and gender, but the heterogeneity existed and could not be fully explained.

CONCLUSION: IPF and DM may be associated, but the causal relationship remains indeterminate till now. Further rigorously designed studies are required to confirm the present findings and investigate the possible mechanisms behind the effect of DM on IPF.

PMID:34103046 | DOI:10.1186/s12931-021-01760-6

BMC Pulm Med. 2021 Jun 8;21(1):193. doi: 10.1186/s12890-021-01559-7.

NO ABSTRACT

PMID:34103038 | DOI:10.1186/s12890-021-01559-7

Chest. 2021 Jun 5:S0012-3692(21)01090-4. doi: 10.1016/j.chest.2021.05.058. Online ahead of print.

NO ABSTRACT

PMID:34102142 | DOI:10.1016/j.chest.2021.05.058

Histopathology. 2021 Jun 8. doi: 10.1111/his.14427. Online ahead of print.

ABSTRACT

BACKGROUND: The recent recognition of the cicatricial organizing pneumonia (ciOP) indicates that the ciOP may resemble or simulate fibrotic interstitial pneumonia; however, there has been great uncertainty regarding the affected populations, pathogenesis, clinical relevance, and characteristics. In this study, we compared the characteristics of fibrotic interstitial pneumonia with and without ciOP.

METHOD: We enrolled 121 patients from the consultation archive whose pathological findings were fibrotic interstitial pneumonia and for whom follow-up clinical data were available. We reviewed these cases histopathologically and classified them according to whether or not they showed ciOP. We compared the clinicopathological features between the two groups.

RESULT: CiOP histopathologically characterized by deposition of dense collagenous fibers within the alveolar space without destruction of the lung structure was found in 48 patients (39.7%). None of the cases with ciOP experienced acute exacerbation during 12 months follow-up. The group with ciOP had more severe diffusion impairment but this, along with restrictive ventilatory impairment, improved significantly compared to the group without ciOP.

CONCLUSION: CiOP is a histopathological finding commonly found in fibrotic interstitial pneumonia. It does not relate to acute exacerbation or decrease in pulmonary function.

PMID:34101227 | DOI:10.1111/his.14427