Front Endocrinol (Lausanne). 2021 Nov 25;12:765201. doi: 10.3389/fendo.2021.765201. eCollection 2021.

ABSTRACT

Patients with diabetes are over-represented among the total cases reported with "idiopathic" pulmonary fibrosis (IPF). This raises the question, whether this is an association only or whether diabetes itself can cause pulmonary fibrosis. Recent studies in mouse models of type 1 and type 2 diabetes demonstrated that diabetes causes pulmonary fibrosis. Both types of diabetes trigger a cascade, starting with increased DNA damage, an impaired DNA repair, and leading to persistent DNA damage signaling. This response, in turn, induces senescence, a senescence-associated-secretory phenotype (SASP), marked by the release of pro-inflammatory cytokines and growth factors, finally resulting in fibrosis. Restoring DNA repair drives fibrosis into remission, thus proving causality. These data can be translated clinically to patients with type 2 diabetes, characterized by long-term diabetes and albuminuria. Hence there are several arguments, to substitute the term "idiopathic" pulmonary fibrosis (IPF) in patients with diabetes (and exclusion of other causes of lung diseases) by the term "diabetes-induced pulmonary fibrosis" (DiPF). However, future studies are required to establish this term and to study whether patients with diabetes respond to the established therapies similar to non-diabetic patients.

PMID:34899603 | PMC:PMC8655305 | DOI:10.3389/fendo.2021.765201

Biomater Sci. 2021 Dec 13. doi: 10.1039/d1bm01362a. Online ahead of print.

ABSTRACT

The identification of paracrine factors secreted by transplanted mesenchymal stem cells (MSCs) during the treatment of idiopathic pulmonary fibrosis (IPF) is essential for understanding the role of MSCs in therapy. Herein, we report a facile and efficient strategy for in vivo tracking the secretion of hepatocyte growth factor (HGF) in MSCs during IPF therapy. In our strategy, a novel nanoflare tracer consisting of gold nanoparticles (AuNPs), complementary sequences and dye-labeled recognition sequences is developed. Briefly, the AuNPs are functionalized with oligonucleotide complementary sequences hybridized to the organic dye-labeled recognition sequences, where the organic fluorophores are in close proximity to the AuNPs. In the absence of targets, the dye and AuNPs are separated from each other, inducing the quenching of the fluorescence signal. However, in the presence of targets, the recognition sequences gradually fall off from the AuNPs, causing the fluorescence signal to rise. In brief, in vivo monitoring of the dynamic expression of HGF mRNA in transplanted MSCs during IPF therapy in the current work may provide new insight into the paracrine process of the transplanted MSCs, thereby advancing the MSC-based IPF therapy toward clinical applications.

PMID:34897301 | DOI:10.1039/d1bm01362a

Ugeskr Laeger. 2021 Dec 6;183(49):V04210348.

ABSTRACT

Numerous studies have shown that perioperative heparin bridging in patients treated with a vitamin K antagonist leads to an increased incidence of bleeding and so far, there is no evidence that it leads to a significant reduction in postoperative thromboembolism as summarised in this review. Prophylactic dosage of heparin is recommended after major surgery. Heparin bridging is not relevant in patients receiving a direct oral anticoagulant due to the rapid onset and offset of action of DOACs.

PMID:34895441

BMC Pulm Med. 2021 Dec 11;21(1):411. doi: 10.1186/s12890-021-01783-1.

ABSTRACT

BACKGROUND: Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic therapy (grouping nintedanib and pirfenidone together) in patients with IPF versus patients with progressive lung fibrosis not classified as IPF.

STUDY DESIGN AND METHODS: A search of databases including MEDLINE, EMBASE, PubMed, and clinicaltrials.gov was conducted. Studies were included if they were randomised controlled trials of pirfenidone or nintedanib in adult patients with IPF or non-IPF patients, and with extractable data on mortality or decline in forced vital capacity (FVC). Random effects meta-analyses were performed on changes in FVC and where possible on mortality in the selected studies.

RESULTS: 13 trials of antifibrotic therapy were pooled in a meta-analysis (with pirfenidone and nintedanib considered together as anti-fibrotic therapy). The change in FVC was expressed as a standardised difference to allow pooling of percentage and absolute changes. The mean effect size in the IPF studies was - 0.305 (SE 0.043) (p < 0.001) and in the non-IPF studies the figures were - 0.307 (SE 0.063) (p < 0.001). There was no evidence of any difference between the two groups for standardised rate of FVC decline (p = 0.979). Pooling IPF and non-IPF showed a significant reduction in mortality, with mean risk ratio of 07.01 in favour of antifibrotic therapy (p = 0.008). A separate analysis restricted to non-IPF did not show a significant reduction in mortality (risk ratio 0.908 (0.547 to 1.508), p = 0.71.

INTERPRETATION: Anti-fibrotic therapy offers protection against the rate of decline in FVC in progressive lung fibrosis, with similar efficacy shown between the two anti-fibrotic agents currently in clinical use. There was no significant difference in efficacy of antifibrotic therapy whether the underlying condition was IPF or non-IPF with progressive fibrosis, supporting the hypothesis of a common pathogenesis. The data in this analysis was insufficient to be confident about a reduction in mortality in non-IPF with anti-fibrotic therapy. Trial Registration PROSPERO, registration number CRD42021266046.

PMID:34895203 | DOI:10.1186/s12890-021-01783-1

J Med Chem. 2021 Dec 13. doi: 10.1021/acs.jmedchem.1c01716. Online ahead of print.

ABSTRACT

As a result of emerging biological data suggesting that within the c-Jun N-terminal kinase (JNK) family, JNK1 and not JNK2 or JNK3 may be primarily responsible for fibrosis pathology, we sought to identify JNK inhibitors with an increased JNK1 bias relative to our previous clinical compound tanzisertib (CC-930). This manuscript reports the synthesis and structure-activity relationship (SAR) studies for a novel series of JNK inhibitors demonstrating an increased JNK1 bias. SAR optimization on a series of 2,4-dialkylamino-pyrimidine-5-carboxamides resulted in the identification of compounds possessing low nanomolar JNK inhibitory potency, overall kinome selectivity, and the ability to inhibit cellular phosphorylation of the direct JNK substrate c-Jun. Optimization of physicochemical properties in this series resulted in compounds that demonstrated excellent systemic exposure following oral dosing, enabling in vivo efficacy studies and the selection of a candidate for clinical development, CC-90001, which is currently in clinical trials (Phase II) in patients with idiopathic pulmonary fibrosis (NCT03142191).

PMID:34894681 | DOI:10.1021/acs.jmedchem.1c01716

Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021:5446-5449. doi: 10.1109/EMBC46164.2021.9630936.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that can lead to chronic arterial hypoxemia, hypercapnia, and dyspnea. To improve clinical symptoms in IPF patients, supplemental oxygen (SupplO2) has been prescribed with the aim to maintain SpO2 level, and consequently to relieve dyspnea, increase physical activity and improve quality of life. In this study, we investigated the effect of disease and short-term SupplO2 on cardiovascular and respiratory autonomic regulation. Linear and nonlinear indices were extracted from the beat-to-beat variability of heart rate (HR), systolic (SYS) blood pressure and respiration (RESP) in IPF patients and healthy subjects spontaneously breathing ambient air (AA) and during SupplO2 at 3 L/min. It was found that the effects on autonomic nervous systems (ANS) regulation were better demonstrated by the Granger causality (GC) method. GC was significantly higher (p<0.01) in patients compared to controls for the interactions RESP→SYS and BBI→SYS.Clinical Relevance-Short-term SupplO2 in IPF could adversely affect systolic blood pressure variability in particular. This study may help in the management of SupplO2 administration.

PMID:34892358 | DOI:10.1109/EMBC46164.2021.9630936

J Ethnopharmacol. 2021 Dec 7:114901. doi: 10.1016/j.jep.2021.114901. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Pheretima is a traditional Chinese medicine that could treat various lung diseases such as asthma, pneumonia, and lung cancer effectively; however, limited studies on the use of Pheretima protein in the treatment of lung diseases have been conducted to date.

AIM OF THE STUDY: The aim of this study was to explain the antipulmonary fibrosis mechanism of the Pheretima protein and elucidate its possible cell signaling pathways.

MATERIAL AND METHODS: Fresh pheretima was freeze-dried to obtain the Pheretima protein. Divide C57BL/6 mice into control and bleomycin (BLM)-induced models, pirfenidone, and Pheretima protein-treatment groups. Three weeks later, they were treated with H&E and Masson's trichrome staining to assess lung injury and fibrosis. Pulmonary fibrosis was assessed using immunohistochemistry (IHC), realtime-PCR (RT-PCR), and western blotting. Inflammation was assessed using the alveolar lavage fluid.

RESULTS: Pheretima protein inhibited epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition and reduced inflammation. It also reduced the levels of Smad2/3, pSmad2/3, and transforming growth factor-beta 1 (TGF-β1). Thus, our results indicate that Pheretima protein can alleviate BLM-induced pulmonary fibrosis in a mouse model.

CONCLUSION: Pheretima protein inhibits ECM, EMT, and antiinflammatory markers, which in turn ameliorates BLM-induced pulmonary fibrosis. Preliminary mechanistic studies indicated that Pheretima protein can exert its biological activity by downregulating the TGF-β1/Smad2/3 pathway.

PMID:34890730 | DOI:10.1016/j.jep.2021.114901

Toxicol Appl Pharmacol. 2021 Dec 7:115817. doi: 10.1016/j.taap.2021.115817. Online ahead of print.

ABSTRACT

Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in Western countries. Pirfenidone (PFD), an orally bioavailable pyridone derivative, is clinically used for idiopathic pulmonary fibrosis treatment and has antifibrotic, anti-inflammatory, and antioxidant effects. Here we examined the PFD effect on APAP-induced liver injury. In a murine model, APAP caused serum alanine aminotransferase elevation attenuated by PFD treatment. We performed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and vital propidium iodide (PI) stainings simultaneously. APAP induced TUNEL-positive/PI-negative necrosis around the central vein and subsequent TUNEL-negative/PI-positive oncotic necrosis with hemorrhage and caused the upregulation of hypercoagulation- and hypoxia-associated gene expressions. PFD treatment suppressed these findings. Western blotting revealed PFD suppressed APAP-induced c-Jun N-terminal kinase (JNK) phosphorylation despite no effect on JNK phosphatase expressions. In conclusion, simultaneous TUNEL and vital PI staining is useful for discriminating APAP-induced necrosis from typical oncotic necrosis. Our results indicated that PFD attenuated APAP-induced liver injury by suppressing TUNEL-positive necrosis by directly blocking JNK phosphorylation. PFD is promising as a new option to prevent APAP-induced liver injury.

PMID:34890640 | DOI:10.1016/j.taap.2021.115817

Chin Med J (Engl). 2021 Dec 10. doi: 10.1097/CM9.0000000000001834. Online ahead of print.

NO ABSTRACT

PMID:34890381 | DOI:10.1097/CM9.0000000000001834

Ann Am Thorac Soc. 2021 Dec 10. doi: 10.1513/AnnalsATS.202107-897OC. Online ahead of print.

ABSTRACT

RATIONALE: The diagnosis of idiopathic pulmonary fibrosis (IPF) remains challenging and can result in delayed or misdiagnosis. IPF diagnosis is based upon the presence of either a radiographic or histologic usual interstitial pneumonia (UIP) pattern in the absence of an identifiable etiology. The Envisia Genomic Classifier is a clinically validated molecular diagnostic test that identifies UIP in transbronchial biopsies.

OBJECTIVE: To determine the impact of the Envisia Genomic Classifier on physician's clinical decision making in the diagnosis and management of IPF.

METHODS: This prospective randomized decision impact survey was designed to test the hypothesis that including an Envisia UIP positive (UIP+) result will increase IPF diagnoses, diagnostic confidence levels, and the recommendation for antifibrotic therapy. The survey included patients from the BRAVE study who had an HRCT scan without a typical UIP pattern, an Envisia UIP+ result, and a final diagnosis of IPF by multidisciplinary team discussion. Each case was presented in three different formats: a pre-post cohort where each case is presented initially without and then with Envisia, and two independent cohorts where each case is presented without and with Envisia, respectively.

RESULTS: U.S. based pulmonologists from community and academic centers in geographically diverse practices were approached for inclusion in this study. 103 (65%) US-based pulmonologists met the inclusion criteria and provided 605 case reviews of 11 patient cases. The number of IPF diagnoses increased with Envisia by an absolute difference of 39% from 47 (30%) pre-Envisia to 107 (69%) post-Envisia in the pre-post cohort and by 13% in the independent cohorts. High confidence (> 90%) of ILD diagnoses was more commonly seen with Envisia in both the pre-post cohort and in the independent cohorts. Recommendation for antifibrotic treatment increased with Envisia by an absolute difference of 36% from 15 (10%) pre-Envisia to 72 (46.4%) post-Envisia in the pre-post cohort and by 11% in the independent cohorts.

CONCLUSIONS: This decision impact survey suggests the clinical utility of the Envisia Classifier by demonstrating a significant increase in IPF diagnoses, diagnostic confidence, and recommendation for antifibrotic therapies to assist physicians to effectively manage patients to improve outcomes of patients with IPF.

PMID:34889723 | DOI:10.1513/AnnalsATS.202107-897OC

Front Med (Lausanne). 2021 Nov 23;8:668024. doi: 10.3389/fmed.2021.668024. eCollection 2021.

ABSTRACT

Background: Diversity in response on exposure to severe acute respiratory syndrome coronavirus 2 may be related to the innate immune response in the elderly. The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. The high expressing T-allele is a risk allele for the non-infectious aging lung disease idiopathic pulmonary fibrosis (IPF). We investigated if MUC5B rs35705950 associates with severe COVID-19. Methods: In this retrospective candidate gene case-control study we recruited 108 Dutch patients (69% male, median age 66 years, 77% white) requiring hospitalization for COVID-19 (22% ICU stay, 24% died). For validation, genotypes were obtained from the UK-Biobank (n = 436, 57% male, median age 70 years, 27% died), for replication data from the severe COVID-19 GWAS group from Italy (n = 835) and Spain (n = 775) was used, each with a control cohort (n = 356,735, n = 1,255, n = 950, respectively). MUC5B association analysis was performed including adjustment for age and sex. Results: The rs35705950 T-allele frequency was significantly lower in Dutch white patients (n = 83) than in controls (0.04 vs. 0.10; p = 0.02). This was validated in the UK biobank cohort (0.08 vs. 0.11; p = 0.001). While age and sex differed significantly between cases and control, comparable results were obtained with age and sex as confounding variables in a multivariate analysis. The association was replicated in the Italian (p = 0.04), and Spanish (p = 0.03) case-control cohorts. Meta-analysis showed a negative association for the T-allele with COVID-19 (OR = 0.75 (CI: 0.67-0.85); p = 6.63 × 10-6). Conclusions: This study shows that carriage of the T-allele of MUC5B rs35705950 confers protection from development of severe COVID-19. Because the T-allele is a known risk allele for IPF, this study provides further evidence for the existence of trade-offs between optimal mucin expression levels in the aging lung.

PMID:34888316 | PMC:PMC8650310 | DOI:10.3389/fmed.2021.668024

Sultan Qaboos Univ Med J. 2021 Nov;21(4):660-663. doi: 10.18295/squmj.4.2021.046. Epub 2021 Nov 25.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, represents an unprecedented global threat. We report a 78-year-old male patient who presented to the Emergency Department at a tertiary care hospital in Muscat, Oman, in June 2020 with a one-day history of right chest pain and severe breathlessness. The patient was an ex-smoker and known to have idiopathic pulmonary fibrosis (IPF) with two previous pneumothoraces in the left lung. On presentation, the patient was breathless with an oxygen saturation of 90% on room air. Chest X-ray demonstrated bilateral lung infiltrates and right-sided pneumothorax. The patient tested positive for SARS CoV 2. A chest drain was placed which resulted in good resolution of the pneumothorax. The patient's condition improved remarkably and he was discharged after 17 days of hospitalisation. To the best of the authors' knowledge, this was the first case of pneumothorax reported in a patient infected with COVID-19 who was known to have underlying IPF.

PMID:34888092 | PMC:PMC8631211 | DOI:10.18295/squmj.4.2021.046

Front Immunol. 2021 Nov 23;12:782074. doi: 10.3389/fimmu.2021.782074. eCollection 2021.

ABSTRACT

Mitochondria are essential organelles for cell metabolism, growth, and function. Mitochondria in lung cells have important roles in regulating surfactant production, mucociliary function, mucus secretion, senescence, immunologic defense, and regeneration. Disruption in mitochondrial physiology can be the central point in several pathophysiologic pathways of chronic lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and asthma. In this review, we summarize how mitochondria morphology, dynamics, redox signaling, mitophagy, and interaction with the endoplasmic reticulum are involved in chronic lung diseases and highlight strategies focused on mitochondrial therapy (mito-therapy) that could be tested as a potential therapeutic target for lung diseases.

PMID:34887870 | PMC:PMC8649841 | DOI:10.3389/fimmu.2021.782074

Transplant Proc. 2021 Dec 6:S0041-1345(21)00805-8. doi: 10.1016/j.transproceed.2021.10.009. Online ahead of print.

ABSTRACT

BACKGROUND: This study aims to assess the incidence of primary lung cancer in the native lung and its impact on survival in patients undergoing single lung transplantation (SLT).

METHODS: This study retrospectively analyzed 161 SLTs performed between June 2012 and June 2019. The incidence of carcinoma in the native lung and its influence on patient survival was determined. Recipient variables, tumor stage, and survival were analyzed and compared between patients with and without native lung cancer. The analysis was adjusted for transplant indication. Both univariable and multivariable analyses were performed. The present study followed the Declaration of Helsinki Ethical Principles for Medical Research involving human subjects.

RESULTS: There were 161 patients (126 men/35 women; 57 ± 7 years) transplanted for chronic obstructive pulmonary disease (COPD) (n = 72), idiopathic pulmonary fibrosis (IPF) (n = 77), or other indications (n = 12). Eleven patients with COPD (7%) developed lung cancer in the native lung after SLT. Lung cancer did not appear in any of the SLTs for pulmonary fibrosis. Five participants were in stages I/II and underwent lung resection, and 6 participants were in stages III/IV and underwent chemotherapy/radiotherapy. Survival (1, 3, and 5 years) without vs with native lung carcinoma in patients with COPD was 89%, 86%, and 80% vs 86%, 71%, and 51% (P = .04). The occurrence of carcinoma in the native lung predicted survival in patients with COPD (odds ratio [OR]: 2.55; P = .07).

CONCLUSIONS: Lung cancer in the native lung is a frequent and devastating complication after SLT in patients with COPD, which might negatively affect long-term survival. This should be considered when choosing the transplant procedure for patients with COPD.

PMID:34887097 | DOI:10.1016/j.transproceed.2021.10.009

Clin Radiol. 2021 Dec 6:S0009-9260(21)00535-3. doi: 10.1016/j.crad.2021.11.006. Online ahead of print.

ABSTRACT

AIM: To compare the machine learning computed tomography (CT) quantification tool, Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER) to pulmonary function testing (PFT) in assessing idiopathic pulmonary fibrosis (IPF) for patients undergoing treatment and determine the effects of limited (LD) and ultra-low dose (ULD) CT on CALIPER performance.

MATERIALS AND METHODS: Thirty-eight IPF patients underwent PFT and standard, LD, and ULD CT. CALIPER classified each CT voxel into either vessel-related structures (VRS), normal, reticular (R), honeycomb (HC) or ground-glass (GG) features. CALIPER-derived interstitial lung disease (ILD) extent represented the sum of GG, R and HC values. Repeated-measures correlation coefficient (ρrm) and 95% confidence interval (CI) evaluated CALIPER features correlation with PFT. Lin's concordance correlation coefficient (CCC) assessed concordance of CALIPER parameters across different CT dosages.

RESULTS: Twenty patients completed 12 months of follow-up. CALIPER ILD correlated significantly with percent predicted (%) forced vital capacity (FVC) and forced expiratory volume in 1 second (%FEV1; p=0.004, ρrm -0.343, 95% CI [-0.547, -0.108] and 0.008, -0.321, [-0.518, -0.07], respectively). VRS significantly correlated with %FVC and %FEV1 (p=0.000, ρrm -0.491, 95% CI [-0.685, -0.251] and -0.478, 0.000, [-0.653, -0.231], respectively). There was near perfect LD and moderate ULD concordance with standard dose CT for both ILD (CCC 0.995, 95% CI 0.988-0.999 and 0.9, 0.795-0.983, respectively) and VRS (CCC 0.989, 95% CI 0.963-0.997 and 0.915, 0.806-0.956, respectively).

CONCLUSIONS: CALIPER parameters correlate well with PFTs for evaluation of IPF in patients undergoing anti-fibrotic treatment without being influenced by dose variation. CALIPER may serve as a robust, objective adjunct to PFTs in assessing anti-fibrotic treatment related changes.

PMID:34887070 | DOI:10.1016/j.crad.2021.11.006

BMC Vet Res. 2021 Dec 9;17(1):380. doi: 10.1186/s12917-021-03081-8.

ABSTRACT

BACKGROUND: In humans with idiopathic pulmonary fibrosis (IPF), specific thoracic computed tomographic (CT) features in the correct clinical context may be used in lieu of histologic examination. Cats develop an IPF-like condition with similar features to humans. As few cats have invasive lung biopsies, CT has appeal as a surrogate diagnostic, showing features consistent with architectural remodeling supporting "end-stage lung".

CASE PRESENTATION: A 1-year-old female spayed Domestic Shorthair cat presenting with progressive respiratory clinical signs and thoracic CT changes (reticular pattern, parenchymal bands, subpleural interstitial thickening, pleural fissure thickening, subpleural lines and regions of increased attenuation with traction bronchiectasis and architectural distortion) consistent with reports of IPF was given a grave prognosis for long-term survival. The cat was treated with prednisolone, fenbendazole, pradofloxacin and clindamycin. Five months later, while still receiving an anti-inflammatory dose of prednisolone, the cat was re-evaluated with owner-reported absent respiratory clinical signs. Thoracic CT demonstrated resolution of lung patterns consistent with fibrosis.

CONCLUSIONS: Fibrotic lung disease is irreversible. Despite this cat having compatible progressive respiratory signs and associated lung patterns on thoracic CT scan, these abnormalities resolved with non-specific therapy and time, negating the possibility of IPF. While the cause of the distinct CT lesions that ultimately resolved was not determined, infection was suspected. Experimental Toxocara cati infection shows overlapping CT features as this cat and is considered a treatable disease. Improvement of CT lesions months after experimental heartworm-associated respiratory disease in cats has been documented. Reversibility of lesions suggests inflammation rather than fibrosis was the cause of the thoracic CT lesions. This cat serves as a lesson that although thoracic CT has been advocated as a surrogate for histopathology in people with IPF, additional studies in cats are needed to integrate CT findings with signalment, other clinicopathologic features and therapeutic response before providing a diagnosis or prognosis of fibrotic lung disease.

PMID:34886851 | DOI:10.1186/s12917-021-03081-8

Cancers (Basel). 2021 Nov 26;13(23):5958. doi: 10.3390/cancers13235958.

ABSTRACT

For almost the entire period of the last two decades, translational research in the area of integrin-targeting radiopharmaceuticals was strongly focused on the subtype αvβ3, owing to its expression on endothelial cells and its well-established role as a biomarker for, and promoter of, angiogenesis. Despite a large number of translated tracers and clinical studies, a clinical value of αvβ3-integrin imaging could not be defined yet. The focus of research has, thus, been moving slowly but steadily towards other integrin subtypes which are involved in a large variety of tumorigenic pathways. Peptidic and non-peptidic radioligands for the integrins α5β1, αvβ6, αvβ8, α6β1, α6β4, α3β1, α4β1, and αMβ2 were first synthesized and characterized preclinically. Some of these compounds, targeting the subtypes αvβ6, αvβ8, and α6β1/β4, were subsequently translated into humans during the last few years. αvβ6-Integrin has arguably attracted most attention because it is expressed by some of the cancers with the worst prognosis (above all, pancreatic ductal adenocarcinoma), which substantiates a clinical need for the respective theranostic agents. The receptor furthermore represents a biomarker for malignancy and invasiveness of carcinomas, as well as for fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and probably even for Sars-CoV-2 (COVID-19) related syndromes. Accordingly, the largest number of recent first-in-human applications has been reported for radiolabeled compounds targeting αvβ6-integrin. The results indicate a substantial clinical value, which might lead to a paradigm change and trigger the replacement of αvβ3 by αvβ6 as the most popular integrin in theranostics.

PMID:34885066 | DOI:10.3390/cancers13235958

Int J Mol Sci. 2021 Nov 30;22(23):12955. doi: 10.3390/ijms222312955.

ABSTRACT

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1-7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1-7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.

PMID:34884756 | DOI:10.3390/ijms222312955

J Clin Med. 2021 Nov 26;10(23):5562. doi: 10.3390/jcm10235562.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common and severe form within the group of idiopathic interstitial pneumonias. It is characterized by repetitive alveolar injury in genetically susceptible individuals and abnormal wound healing, leading to dysregulated bronchiolar proliferation and excessive deposition of extracellular matrix, causing complete architectural distortion and fibrosis. Epithelial-to-mesenchymal transition is considered an important pathogenic event, a phenomenon also observed in various malignant neoplasms, in which tumor cells express programmed death-ligand one (PD-L1). The aim of this study was to assess the presence of PD-L1 in patients with IPF and other interstitial lung diseases (ILDs).

METHOD: Patients with a clinically and radiologically suspected idiopathic interstitial pneumonia or other ILDs undergoing transbronchial cryobiopsy to confirm the diagnosis at the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, were included in this prospective observational study. Cellular membrane PD-L1 expression in epithelial cells was determined using the DAKO PD-L1 IHC 22C3 PharmDx Kit.

RESULTS: Membrane-bound PD-L1 (mPD-L1) was found in twelve (28%) of the forty-three patients with IPF and in five (9%) of the fifty-five patients with other ILDs (p = 0.015). When adjusting for age, gender and smoking status, the odds ratio of having IPF when expressing mPD-L1 in alveolar and/or bronchiolar epithelial cells was 4.3 (CI: 1.3-14.3).

CONCLUSION: Expression of mPD-L1 in epithelial cells in the lung parenchymal zones was detected in a consistent subgroup of patients with IPF compared to other interstitial pneumonias. Larger studies are needed to explore the role of mPD-L1 in patients with IPF.

PMID:34884264 | DOI:10.3390/jcm10235562

ERJ Open Res. 2021 Dec 6;7(4):00345-2021. doi: 10.1183/23120541.00345-2021. eCollection 2021 Oct.

ABSTRACT

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is relevant for the prognosis in patients with RA. Nintedanib, which inhibits both receptor and non-receptor type tyrosine kinases, is an antifibrotic drug for the treatment of progressive fibrosing ILDs, such as idiopathic pulmonary fibrosis and systemic sclerosis-associated interstitial lung disease. Little is known about the effects of nintedanib on RA-ILD. We examined the characteristics of a novel induced RA-ILD (iRA-ILD) mouse model and the effects of nintedanib on the model. D1CC×D1BC mice are highly susceptible to arthritogenic antigens, such as bovine type II collagen, resulting in severe inflammatory arthritis. ILD develops after joint inflammation is alleviated. Serum surfactant protein D levels were monitored as an ILD marker. Nintedanib was orally administered to iRA-ILD mice for 2 months. The iRA-ILD model showed similar symptoms to those in patients with RA-ILD. The histopathological features of pulmonary disorder resembled nonspecific interstitial pneumonia, but with metaplastic epithelium. Histopathological analysis revealed that in addition to reducing fibrosis, nintedanib suppressed M2 macrophage polarisation and hyperplasia of Type 2 alveolar epithelial cells. The metaplastic epithelium acquired invasiveness because of the expression of E-cadherin, MMP7, Tgf-β, Col1a1, Padi2 and Padi4. Moreover, citrullinated peptides were detected in these invasive epithelial cells as well as in the bronchiolar epithelium. Administration of nintedanib reduced the expression of Pad4 and citrullinated peptides and eliminated invasive epithelial cells. The broad inhibitory effects of nintedanib on tyrosine kinases may contribute to the overall improvement in RA-ILD, including epithelial abnormalities associated with progressive lung fibrosis.

PMID:34881329 | PMC:PMC8646002 | DOI:10.1183/23120541.00345-2021