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

Pulm Pharmacol Ther. 2021 Jun 21:102051. doi: 10.1016/j.pupt.2021.102051. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Although anti-fibrotic treatments, such as pirfenidone, are available that reduce the rate of disease progression, these medications have limitations in tolerability, and IPF patients still have poor prognoses. GDC-3280, an orally available small molecule that was designed to improve upon pirfenidone's activity, has anti-fibrotic activity in animal models. This first-in-human, phase 1 trial evaluated GDC-3280 to determine its safety, tolerability, and pharmacokinetics (PK).

METHODS: Single and multiple ascending-doses of GDC-3280 were administered to healthy volunteers in two parts. Part A consisted of 6 treatment groups, each receiving a single, oral dose of GDC-3280 (25-1600 mg) or placebo in the fasted state. Part A also assessed the effect of food and coadministration of a proton pump inhibitor (rabeprazole) on the tolerability and PK of single doses of 400- and 800-mg GDC-3280. Part B consisted of 3 treatment groups who received either 200- or 275-mg GDC-3280 twice daily or 525-mg once daily after a low-fat meal for 7 days. The trial monitored treatment-emergent adverse events (TEAEs) and assessed the pharmacokinetics of GDC-3280 in blood and urine samples.

RESULTS: Fifty-six subjects (42 GDC-3280, 14 placebo) in Part A and 24 subjects (18 GDC-3280, 6 placebo) in Part B received treatment. No deaths, serious adverse events, or dose-limiting adverse events occurred, and no subjects withdrew due to a TEAE. In both Parts A and B, most TEAEs were mild. The most frequent TEAEs in Part A were headache and nausea. TEAEs occurred more often when GDC-3280 was administered with food. Pretreatment and coadministration with rabeprazole had no effect on GDC-3280 tolerability. In Part B, the most frequent TEAEs were nausea, dizziness, nasal congestion, and cough. Transient, treatment-related increases in serum creatinine occurred at doses greater than 400 mg in Part A (12%-18% from baseline) and after multiple doses in each group in Part B (20%-34% from baseline). GDC-3280 was generally readily absorbed with a median tmax < 4.0 hours following single- or repeat-dose oral administration. In Part A, less-than-dose-proportional increases in systemic exposure occurred, and in Part B, dose-proportional increases occurred within the dose range tested. At doses of 200 mg or lower, more than 50%-70% of orally administered doses were recovered in urine as unchanged GDC-3280 when subjects received a single dose of GDC-3280, suggesting renal excretion is one of the major routes of elimination. Administration of single doses of 400- and 800-mg GDC-3280 after a meal caused statistically significant increases in exposure due to increased rates of absorption compared to the fasted state. Pretreatment and coadministration of rabeprazole dosing led to decreases in exposure compared to GDC-3280 alone, indicating a weak drug-drug interaction. Following repeat dose administration, steady-state plasma concentrations of GDC-3280 were achieved within 2 days with an apparent terminal half-life (t1/2) between 5 and 6 hours.

CONCLUSIONS: Single and multiple doses of GDC-3280 were generally well tolerated, with acceptable safety and pharmacokinetic profiles that support twice-daily, oral administration with food in future clinical trials.

PMID:34166834 | DOI:10.1016/j.pupt.2021.102051

Ann Transl Med. 2021 May;9(10):900. doi: 10.21037/atm-20-4934.

ABSTRACT

There is a very well-established and complex interplay between gastroesophageal reflux and lung disease. This is particularly true in end-stage lung disease and post-lung transplant patients. Numerous studies have shown that in patients who are undergoing pre-lung transplant evaluations for diseases such as idiopathic pulmonary fibrosis (IPF), emphysema, connective tissue disease, there is a high prevalence of gastroesophageal reflux and esophageal dysmotility. Post-lung transplant, many of the reflux issues persist or worsen, and there is some evidence to suggest that this leads to worsened long-term allograft function and bronchiolitis obliterans. Anti-reflux operations in patients with lung disease have been shown to be safe in both the pre and post-lung transplant setting and lead to improved reflux symptoms, as well as protecting against reflux induced allograft dysfunction in the post-lung transplant patients. Barrett's esophagus and esophageal malignancy are also not unheard of in these patients, and select patients may benefit from operative intervention. This review discusses the links between gastroesophageal reflux and lung transplant patients in both the pre and post-transplant setting. We also review the approach to the workup of esophageal disease in the pre-lung transplant setting as well as the surgical management of this unique group of patients.

PMID:34164534 | PMC:PMC8184450 | DOI:10.21037/atm-20-4934

SAGE Open Med. 2021 Jun 6;9:20503121211023357. doi: 10.1177/20503121211023357. eCollection 2021.

ABSTRACT

BACKGROUND: The INPULSIS trials revealed that nintedanib reduced the decline in lung function in patients with idiopathic pulmonary fibrosis. We aimed to evaluate the efficacy and safety of nintedanib in Japanese idiopathic pulmonary fibrosis patients in real-world settings.

METHOD: Medical records of idiopathic pulmonary fibrosis patients, who received treatment with nintedanib in five institutions between July 2015 and June 2017, were reviewed. Patients with % forced vital capacity ⩾50% and % predicted diffusing capacity of the lung carbon monoxide ⩾30% were classified as the moderate group and those with more impaired lung functions as the severe group.

RESULT: Among 158 patients analyzed, 132 (84.6%) were classified as the moderate group and 26 (15.4%) as the severe group. In the moderate group, changes in forced vital capacity in 12 months were significantly different between before and after nintedanib administration (-253 ± 163 vs -125 ± 235 mL; p = 0.0027). In contrast, changes in forced vital capacity in 12 months were not significantly changed by nintedanib treatment in the severe group (-353 ± 250 vs -112 ± 341 mL; p = 0.2374). Incidence of acute exacerbation was higher in the severe group than in the moderate group (30.8% vs 18.9%). The overall survival of the moderate and the severe groups was 17.2 and 10.1 months.

CONCLUSION: In real-world practice, nintedanib showed comparable efficacy to those observed in previous trials. In the severe group, the efficacy of nintedanib might be limited.

PMID:34164129 | PMC:PMC8188975 | DOI:10.1177/20503121211023357

Am J Physiol Lung Cell Mol Physiol. 2021 Jun 23. doi: 10.1152/ajplung.00615.2020. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis three weeks after intratracheal bleomycin administration. While we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.

PMID:34160296 | DOI:10.1152/ajplung.00615.2020

Respir Res. 2021 Jun 17;22(1):181. doi: 10.1186/s12931-021-01779-9.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients.

METHODS: A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed.

RESULTS: In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01-1.07; IL-8, HR = 1.04, 95% CI 1.01-1.08; MIP-1α, HR = 1.19, 95% CI 1.00-1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02-1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01-1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls.

CONCLUSIONS: CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention).

PMID:34158044 | DOI:10.1186/s12931-021-01779-9

EBioMedicine. 2021 Jun 19;69:103439. doi: 10.1016/j.ebiom.2021.103439. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 has been associated with Interstitial Lung Disease features. The immune transcriptomic overlap between Idiopathic Pulmonary Fibrosis (IPF) and COVID-19 has not been investigated.

METHODS: we analyzed blood transcript levels of 50 genes known to predict IPF mortality in three COVID-19 and two IPF cohorts. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was applied to distinguish high versus low-risk profiles in all cohorts. SAMS cutoffs derived from the COVID-19 Discovery cohort were used to predict intensive care unit (ICU) status, need for mechanical ventilation, and in-hospital mortality in the COVID-19 Validation cohort. A COVID-19 Single-cell RNA-sequencing cohort was used to identify the cellular sources of the 50-gene risk profiles. The same COVID-19 SAMS cutoffs were used to predict mortality in the IPF cohorts.

FINDINGS: 50-gene risk profiles discriminated severe from mild COVID-19 in the Discovery cohort (P = 0·015) and predicted ICU admission, need for mechanical ventilation, and in-hospital mortality (AUC: 0·77, 0·75, and 0·74, respectively, P < 0·001) in the COVID-19 Validation cohort. In COVID-19, 50-gene expressing cells with a high-risk profile included monocytes, dendritic cells, and neutrophils, while low-risk profile-expressing cells included CD4+, CD8+ T lymphocytes, IgG producing plasmablasts, B cells, NK, and gamma/delta T cells. Same COVID-19 SAMS cutoffs were also predictive of mortality in the University of Chicago (HR:5·26, 95%CI:1·81-15·27, P = 0·0013) and Imperial College of London (HR:4·31, 95%CI:1·81-10·23, P = 0·0016) IPF cohorts.

INTERPRETATION: 50-gene risk profiles in peripheral blood predict COVID-19 and IPF outcomes. The cellular sources of these gene expression changes suggest common innate and adaptive immune responses in both diseases.

PMID:34157486 | DOI:10.1016/j.ebiom.2021.103439