Front Endocrinol (Lausanne). 2022 Oct 17;13:1040526. doi: 10.3389/fendo.2022.1040526. eCollection 2022.

ABSTRACT

CTGF is a multifunctional protein and plays different roles in different cells and under different conditions. Pamrevlumab, a monoclonal antibody against CTGF, is an FDA approved drug for idiopathic pulmonary fibrosis (IPF) and Duchenne muscular dystrophy (DMD). Recent studies have shown that CTGF antibodies may potentially serve as a new drug for osteoarthritis (OA). Expression of CTGF is significantly higher in OA joints than in healthy counterparts. Increasing attention has been attracted due to its interesting roles in joint homeostasis. Joint homeostasis relies on normal cellular functions and cell-cell interactions. CTGF is essential for physiological activities of chondrocytes. Abnormal CTGF expression may cause cartilage degeneration. In this review, the physiological functions of CTGF in chondrocytes and related mechanisms are summarized. Changes in the related signaling pathways due to abnormal CTGF are discussed, which are contributing factors to inflammation, cartilage degeneration and synovial fibrosis in OA. The possibility of CTGF as a potential therapeutic target for OA treatment are reviewed.

PMID:36325449 | PMC:PMC9618584 | DOI:10.3389/fendo.2022.1040526

Front Pharmacol. 2022 Oct 17;13:1027332. doi: 10.3389/fphar.2022.1027332. eCollection 2022.

NO ABSTRACT

PMID:36324683 | PMC:PMC9620474 | DOI:10.3389/fphar.2022.1027332

J Med Case Rep. 2022 Nov 2;16(1):404. doi: 10.1186/s13256-022-03619-w.

ABSTRACT

BACKGROUND: We report a case of acute respiratory distress associated with a histological pattern of acute fibrinous and organizing pneumonia, and discuss the possible responsibility of flecainide therapy.

CASE PRESENTATION: A 61-year-old African woman developed a rapidly progressive dyspnea and required admission in the intensive care unit for orotracheal intubation and mechanical ventilation. Chest X-ray examination revealed bilateral infiltrates predominating in the basal part of both lungs. Lung computed tomography disclosed bilateral ground-glass opacities and septal thickening. After exclusion of the most common causes of infectious or immune pneumonia, a toxic origin was investigated and flecainide toxicity was considered. Lung biopsy was consistent with the unusual pattern of acute fibrinous and organizing pneumonia. Clinical and radiological improvement was noted after corticosteroid therapy, but the patient died from septic complications.

CONCLUSION: Flecainide-induced lung injury has rarely been reported in the literature and remains a diagnosis of exclusion. The histological pattern of acute fibrinous and organizing pneumonia has been previously observed with amiodarone. There are no firm guidelines for the treatment of acute fibrinous and organizing pneumonia, but some patients may positively respond to corticosteroids.

PMID:36320087 | DOI:10.1186/s13256-022-03619-w

Mol Divers. 2022 Nov 2. doi: 10.1007/s11030-022-10557-8. Online ahead of print.

ABSTRACT

Discoidin domain receptor 1 (DDR1) (EC Number 2.7.10.1) has recently been considered as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF). However, none of the currently discovered DDR1 inhibitors have been included in clinical studies due to low target specificity or druggability limitations, necessitating various approaches to develop novel DDR1 inhibitors. In this study, to assure target specificity, a docking assessment of the DDR1 crystal structures was undertaken to find the well-differentiated crystal structure, and 4CKR was identified among many crystal structures. Then, using the best pharmacophore model and molecular docking, virtual screening of the ChEMBL database was done, and five potential molecules were identified as promising inhibitors of DDR1. Subsequently, all hit compound complex systems were validated using molecular dynamics simulations and MM/PBSA methods to assess the stability of the system after ligand binding to DDR1. Based on molecular dynamics simulations and hydrogen-bonding occupancy analysis, the DDR1-Cpd2, DDR1-Cpd17, and DDR1-Cpd18 complex systems exhibited superior stability compared to the DDR1-Cpd1 and DDR-Cpd33 complex systems. Meanwhile, when targeting DDR1, the descending order of the five hit molecules' binding free energies was Cpd17 (- 145.820 kJ/mol) > Cpd2 (- 131.818 kJ/mol) > Cpd18 (- 130.692 kJ/mol) > Cpd33 (- 129.175 kJ/mol) > Cpd1 (- 126.103 kJ/mol). Among them, Cpd2, Cpd17, and Cpd18 showed improved binding characteristics, indicating that they may be potential DDR1 inhibitors. In this research, we developed a high-hit rate, effective screening method that serves as a theoretical guide for finding DDR1 inhibitors for the development of IPF therapeutics.

PMID:36322341 | DOI:10.1007/s11030-022-10557-8

BMJ Case Rep. 2022 Nov 1;15(11):e249912. doi: 10.1136/bcr-2022-249912.

ABSTRACT

Organising pneumonia (OP) is a form of interstitial pneumonia characterised by inflammation and scarring leading to obstruction within the small airways and alveoli. Practice guidelines recommend treatment of moderate to severe OP with glucocorticoids; however, there have been cases of steroid-resistant OP successfully treated with rituximab. We describe a case of a woman in her 20s with rheumatoid arthritis who presented with pleuritic chest pain, haemoptysis and dyspnoea on exertion and was diagnosed with OP after multiple radiographic images and biopsies. The patient failed numerous treatment regimens, including corticosteroids, antibiotics and mycophenolate, but was successfully treated with rituximab. This case highlights the importance of identifying new therapeutic agents that will minimise the use of glucocorticoids in the treatment of OP.

PMID:36319035 | PMC:PMC9628664 | DOI:10.1136/bcr-2022-249912

Arch Bronconeumol. 2022 Oct 13:S0300-2896(22)00584-1. doi: 10.1016/j.arbres.2022.09.020. Online ahead of print.

NO ABSTRACT

PMID:36319518 | DOI:10.1016/j.arbres.2022.09.020

Transplant Proc. 2022 Oct 29:S0041-1345(22)00656-X. doi: 10.1016/j.transproceed.2022.10.003. Online ahead of print.

ABSTRACT

BACKGROUND: The outcomes of heart-lung transplant (HLT) are worse than those of heart transplant (HT) and lung transplant alone; this and the availability of mechanical assistance have meant that the indications for HLT have been changing. This study aims to analyze the evolution of indications for HLT in a country of 47 million inhabitants.

METHODS: We performed a retrospective observational study of all HLTs performed in Spain (performed in 2 centers) from 1990 to 2020. The total number of patients included was 1751 (HT 1673 and HLT 78). After clinical adjustment, overall survival was compared between the 2 groups. Seven etiological subgroups were considered within the HLT group: (1) cardiomyopathy with pulmonary hypertension (CM + PH);, (2) Eisenmenger syndrome, (3) congenital heart disease without Eisenmenger syndrome, (4) idiopathic pulmonary arterial hypertension (IPAH), (5) cystic fibrosis, (6) chronic obstructive pulmonary disease (COPD) and/or emphysema), and (7) diffuse interstitial lung disease.

RESULTS: There were a large number of differences between patients with HLT vs HT. HLT had a 2.69-fold increased probability of death in the first year compared with HT. The indications for HLT have changed over the years. In the recent period the indications are mainly congenital heart disease and Eisenmenger syndrome, with some cases of CM + PH. Other indications for HLT have virtually disappeared, mainly lung diseases (IPAH, COPD, cystic fibrosis). Median survival was low in CM + PH (18 days), diffuse interstitial lung disease (29 days), and ischemic heart disease (114 days); intermediate in Eisenmenger syndrome (600 days); and longer in IPAH, COPD and/or emphysema, and cystic fibrosis.

CONCLUSIONS: HLT is a procedure with high mortality. This and mechanical assists mean that the indications have changed over the years. Etiological analysis is of utmost interest to take advantage of organs and improve survival.

PMID:36319494 | DOI:10.1016/j.transproceed.2022.10.003

Am J Respir Cell Mol Biol. 2022 Nov 1. doi: 10.1165/rcmb.2022-0074OC. Online ahead of print.

ABSTRACT

Loss of epithelial integrity, bronchiolarization, and fibroblast activation are key characteristics of idiopathic pulmonary fibrosis (IPF). Prolonged accumulation of basal-like cells in IPF may impact the fibrotic niche to promote fibrogenesis. To investigate their role in IPF, basal cells were isolated from IPF explant and healthy donor lung tissues. Single Cell RNA sequencing was used to assess differentially expressed genes in basal cells. Basal cell and niche interaction was demonstrated with the sLP-mCherry niche labeling system. Luminex assays were used to assess cytokines secreted by basal cells. The role of basal cells in fibroblast activation was studies. 3D organoid culture assays were used to interrogate basal cell effects on AEC2 renewal capacity. Perturbation was used to investigate WNT7A function in vitro and in a repetitive bleomycin model in vivo. We found that WNT7A is highly and specifically expressed in basal-like cells. Proteins secreted by basal cells can be captured by neighboring fibroblasts and AEC2s. Basal cells or basal cell conditioned media activate fibroblasts through WNT7A. Basal cell-derived WNT7A inhibits AEC2 progenitor cell renewal in 3D organoid cultures. Neutralizing antibodies against WNT7A or a small molecule inhibitor of Frizzled signaling abolished basal cell induced fibroblast activation and attenuated lung fibrosis in mice. In summary, basal cells and basal cell-derived WNT7A are key components of the fibrotic niche, providing a unique non-stem cell function of basal cells in IPF progression and a novel targeting strategy for IPF.

PMID:36318668 | DOI:10.1165/rcmb.2022-0074OC

Pharmacoecon Open. 2022 Oct 31. doi: 10.1007/s41669-022-00378-8. Online ahead of print.

ABSTRACT

BACKGROUND: The National Institute for Health and Care Excellence (NICE) is responsible for ensuring that patients in England and Wales can access clinically and cost-effective treatments. However, NICE's processes pose significant reimbursement challenges for treatments for rare diseases. While some orphan medicines have been appraised via the highly specialised technology route, most are appraised via the single technology appraisal programme, a route that is expected to be increasingly used given new more restrictive highly specialised technology criteria. This often results in delays to access owing to differences in applicable thresholds and the single technology appraisal approach being ill-equipped to deal with the inevitable decision uncertainty. NICE recently published their updated methods and process manual, which includes a new severity-of-disease modifier and an instruction to be more flexible when considering uncertainty in rare diseases. However, as the threshold gap between the single technology appraisal and highly specialised technology programmes remains, it is unlikely that these changes alone will address the problem.

OBJECTIVE: We explored the potential impact of quality-adjusted life-year weights in decision making.

METHODS: We explored the impact of NICE's new severity-of-disease modifier weighting and two alternative methods (the use of alternative quality-adjusted life-year weights and the fair rate of return), using three recent single technology appraisals of orphan medicines (caplacizumab, teduglutide and pirfenidone for mild idiopathic pulmonary fibrosis).

RESULTS: Our results suggest NICE's severity-of-disease modifier would not have affected the recommendations. Using alternative methods, based upon achievement of an incremental cost-effectiveness ratio below standard thresholds, patients could have received access to caplacizumab approximately 5 months earlier, and the appraisals for teduglutide and pirfenidone would have resulted in a positive recommendation following appraisal consultation meeting 1 when neither of these products was available over 5 years from the initial submission.

CONCLUSION: Ultimately, moving from a restrictive end-of-life modifier to one based on disease severity is a more equitable approach likely to benefit many therapies, including orphan products. However, NICE's single technology appraisal updates are unlikely to result in faster reimbursement of orphan medicines, nor will they address concerns around market access for orphan medicines in the UK.

PMID:36315388 | DOI:10.1007/s41669-022-00378-8

Respir Res. 2022 Oct 29;23(1):294. doi: 10.1186/s12931-022-02204-5.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) is a major cause of death in patients with idiopathic pulmonary fibrosis (IPF). AE-IPF patients require optimal palliative care; however, the real-world clinical situations are poorly understood. We aimed to survey the palliative care received by AE-IPF patients, especially with respect to opioid use for dyspnea and the end-of-life discussions (EOLd).

METHODS: Self-administered questionnaires were dispatched to 3423 of the certified pulmonary physicians in Japan. They were asked to report a care report form of one patient each with AE-IPF who died very recently about opioid use for dyspnea and EOLd. We further explored the factors associated with the early use of opioids for dyspnea.

RESULTS: Among the 3423 physicians, 1226 (35.8%) returned the questionnaire with the report forms of 539 AE-IPF patients. Of 539 AE-IPF patients, 361 (67.0%) received opioids for dyspnea. Of the 361 patients, 72 (20.0%) received opioids during the initial treatment with an intention of recovery (early use), while 289 (80.0%) did when the recovery was deemed impossible. EOLd was held before the onset of AE in 124 patients (23.0%); however, the majority of patients had EOLd after the admission for AE-IPF. EOLd before the onset of AE was significantly associated with the early use of opioids.

CONCLUSION: In terminally ill AE-IPF patients, opioids are usually administered when the recovery is deemed impossible, and EOLd are rarely held before the onset of AE. Further studies are warranted on the efficacy of opioids for dyspnea and the appropriate timing of EOLd.

PMID:36309741 | DOI:10.1186/s12931-022-02204-5

J Biol Chem. 2022 Oct 26:102644. doi: 10.1016/j.jbc.2022.102644. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and normally fatal disease with limited treatment options. The tyrosine kinase inhibitor Nintedanib has recently been approved for the treatment of IPF, and its effectiveness has been linked to its ability to inhibit a number of receptor tyrosine kinases including the platelet-derived growth factor, vascular endothelial growth factor, and fibroblast growth factor receptors. We show here that Nintedanib also inhibits Salt Inducible Kinase 2 (SIK2), with a similar IC50 to its reported tyrosine kinase targets. Nintedanib also inhibited the related kinases SIK1 and SIK3, although with 12- and 72-fold higher IC50s, respectively. To investigate if the inhibition of SIK2 may contribute to the effectiveness of Nintedanib in treating lung fibrosis, mice with kinase-inactive knockin mutations were tested using a model of bleomycin-induced lung fibrosis. We found that loss of SIK2 activity protects against bleomycin-induced fibrosis, as judged by collagen deposition and histological scoring. Loss of both SIK1 and SIK2 activity had a similar effect to loss of SIK2 activity. Total SIK3 knockout mice have a developmental phenotype making them unsuitable for analysis in this model; however, we determined that conditional knockout of SIK3 in the immune system did not affect bleomycin-induced lung fibrosis. Together, these results suggest that SIK2 is a potential drug target for the treatment of lung fibrosis.

PMID:36309093 | DOI:10.1016/j.jbc.2022.102644

J Cell Mol Med. 2022 Oct 29. doi: 10.1111/jcmm.17600. Online ahead of print.

ABSTRACT

The dysfunction of type II alveolar epithelial cells (AECIIs), mainly manifested by apoptosis, has emerged as a major component of idiopathic pulmonary fibrosis (IPF) pathophysiology. A pivotal mechanism leading to AECIIs apoptosis is mitochondrial dysfunction. Recently, interleukin (IL)-17A has been demonstrated to have a pro-fibrotic role in IPF, though the mechanism is unclear. In this study, we report enhanced expression of IL-17 receptor A (IL-17RA) in AECIIs in lung samples of IPF patients, which may be related to the accumulation of mitochondria in AECIIs of IPF. Next, we investigated this relationship in bleomycin (BLM)-induced PF murine model. We found that IL-17A knockout (IL-17A-/- ) mice exhibited decreased apoptosis levels of AECIIs. This was possibly a result of the recovery of mitochondrial morphology from the improved mitochondrial dynamics of AECIIs, which eventually contributed to alleviating lung fibrosis. Analysis of in vitro data indicates that IL-17A impairs mitochondrial function and mitochondrial dynamics of mouse primary AECIIs, further promoting apoptosis. PTEN-induced putative kinase 1 (PINK1)/Parkin signal-mediated mitophagy is an important aspect of mitochondria homeostasis maintenance. Our data demonstrate that IL-17A inhibits mitophagy and promotes apoptosis of AECIIs by decreasing the expression levels of PINK1. We conclude that IL-17A exerts its pro-fibrotic effects by inducing mitochondrial dysfunction in AECIIs by disturbing mitochondrial dynamics and inhibiting PINK1-mediated mitophagy, thereby leading to apoptosis of AECIIs.

PMID:36308405 | DOI:10.1111/jcmm.17600

Front Pharmacol. 2022 Oct 11;13:1025814. doi: 10.3389/fphar.2022.1025814. eCollection 2022.

ABSTRACT

It is generally accepted that the pathophysiology of idiopathic pulmonary fibrosis (IPF) can be attributed to impaired lung interstitium and alveoli, while airway involvement has rarely been reported. In the present study, we aimed to investigate the actual occurrence of IPF comorbid small airway dysfunction (SAD) and its impact on survival. Data from inpatients diagnosed with IPF at Shanghai Pulmonary Hospital (Shanghai, China) from 2011 to 2021 were retrospectively collected and analyzed. Lung function parameters were used to assess SAD. A total of 243 IPF patients were included in this retrospective study, and 84 cases (84/243, 34.57%) were diagnosed with SAD. The lung histopathology showed that all 48 cases undergoing lung transplantation presented various degrees of airway lesions, of which 18 patients (18/48, 37.5%) diagnosed with SAD before lung transplantation had a higher proportion of airway distortion and obliteration. The possible risk factors associated with IPF comorbid SAD were smoking, male, younger age, and high CT fibrosis and emphysema scores. By univariate Fine-Grey regression, the hazard ratio (HR) of IPF comorbid SAD was 1.725 (95% CI 1.071, 2.777, p < 0.05). After adjusting the CTPF model and GAP model, the value of HR was 1.714 (95% CI 1.043, 2.816, p < 0.05) and 1.731 (95% CI 1.074, 2.788, p < 0.05), respectively. These findings suggested that IPF comorbid SAD was an independent risk factor for the mortality of IPF patients.

PMID:36304160 | PMC:PMC9592693 | DOI:10.3389/fphar.2022.1025814

Int J Environ Res Public Health. 2022 Oct 12;19(20):13099. doi: 10.3390/ijerph192013099.

ABSTRACT

High-resolution CT (HRCT) imaging features of idiopathic interstitial pneumonia (IIP) patients are related to glucocorticoid sensitivity. This study aimed to develop an artificial intelligence model to assess glucocorticoid efficacy according to the HRCT imaging features of IIP. The medical records and chest HRCT images of 150 patients with IIP were analyzed retrospectively. The U-net framework was used to create a model for recognizing different imaging features, including ground glass opacities, reticulations, honeycombing, and consolidations. Then, the area ratio of those imaging features was calculated automatically. Forty-five patients were treated with glucocorticoids, and according to the drug efficacy, they were divided into a glucocorticoid-sensitive group and a glucocorticoid-insensitive group. Models assessing the correlation between imaging features and glucocorticoid sensitivity were established using the k-nearest neighbor (KNN) algorithm. The total accuracy (ACC) and mean intersection over union (mIoU) of the U-net model were 0.9755 and 0.4296, respectively. Out of the 45 patients treated with glucocorticoids, 34 and 11 were placed in the glucocorticoid-sensitive and glucocorticoid-insensitive groups, respectively. The KNN-based model had an accuracy of 0.82. An artificial intelligence model was successfully developed for recognizing different imaging features of IIP and a preliminary model for assessing the correlation between imaging features and glucocorticoid sensitivity in IIP patients was established.

PMID:36293674 | DOI:10.3390/ijerph192013099

Respiration. 2022 Oct 27:1-9. doi: 10.1159/000526575. Online ahead of print.

ABSTRACT

INTRODUCTION: Interstitial lung diseases (ILDs) are associated with a high economic burden, yet prospective data of the German healthcare system are sparse.

OBJECTIVE: We assessed average ILD-related costs of pharmacological and non-pharmacological (hospitalizations, outpatient, rehabilitation, physiotherapy, and medical aids) interventions in ILD.

METHODS: We used data from the multicenter, observational, prospective Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases registry to evaluate adjusted per capita costs and cost drivers for ILD-related healthcare costs over 4 years, using generalized estimating equation regression models.

RESULTS: Idiopathic pulmonary fibrosis (IPF) had the highest annual pharmacological costs >EUR 21,000, followed by connective tissue disease-associated ILD (CTD-ILD) averaging EUR 6,000. Other idiopathic interstitial pneumonias and hypersensitivity pneumonitis averaged below EUR 2,400 and sarcoidosis below EUR 400. There were no significant differences in pharmacological costs over time. Trends in non-pharmacological costs were statistically significant. At year 1, CTD-ILD had the highest costs (EUR 7,700), while sarcoidosis had the lowest (EUR 2,547). By year 4, these declined to EUR 3,218 and EUR 232, respectively. Regarding cost drivers, the ILD subtype had the greatest impact with 75 times higher pharmacological costs in IPF and 4 times higher non-pharmacological costs in CTD-ILD, compared to the reference. Pulmonary hypertension (PH) and gastroesophageal reflux disease (GERD) triggered higher pharmacological costs, and higher values of forced vital capacity % predicted were associated with lower pharmacological and non-pharmacological costs.

CONCLUSION: Stabilizing lung function and reducing the impact of PH and GERD are crucial in reducing the economic burden of ILD. There is an urgent need for effective treatment options, especially in CTD-ILD.

PMID:36302347 | DOI:10.1159/000526575

Redox Biol. 2022 Oct 18;57:102509. doi: 10.1016/j.redox.2022.102509. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by excessive proliferation of fibroblasts and excessive accumulation of extracellular matrix (ECM). Ferroptosis is a novel form of cell death characterized by the lethal accumulation of iron and lipid peroxidation, which is associated with many diseases. Our study addressed the potential role played by ferroptosis and iron accumulation in the progression of pulmonary fibrosis. We found that the inducers of pulmonary fibrosis and injury, namely, bleomycin (BLM) and lipopolysaccharide (LPS), induced ferroptosis of lung epithelial cells. Both the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) alleviated the symptoms of pulmonary fibrosis induced by bleomycin or LPS. TGF-β stimulation upregulated the expression of transferrin receptor protein 1 (TFRC) in the human lung fibroblast cell line (MRC-5) and mouse primary lung fibroblasts, resulting in increased intracellular Fe2+, which promoted the transformation of fibroblasts into myofibroblasts. Mechanistically, TGF-β enhanced the expression and nuclear localization of the transcriptional coactivator tafazzin (TAZ), which combined with the transcription factor TEA domain protein (TEAD)-4 to promote the transcription of TFRC. In addition, elevated Fe2+ failed to induce the ferroptosis of fibroblasts, which might be related to the regulation of iron export and lipid metabolism. Finally, we specifically knocked out TFRC expression in fibroblasts in mice, and compared with those in the control mice, the symptoms of pulmonary fibrosis were reduced in the knockout mice after bleomycin induction. Collectively, these findings suggest the therapeutic potential of ferroptosis inhibitors and iron chelators in treating pulmonary fibrosis.

PMID:36302319 | DOI:10.1016/j.redox.2022.102509

Curr Opin Support Palliat Care. 2022 Oct 28. doi: 10.1097/SPC.0000000000000623. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Chronic cough is common in severe diseases, such as COPD, interstitial lung disease, lung cancer and heart failure, and has a negative effect on quality of life. In spite of this, patients with cough sometimes feel their cough is neglected by healthcare workers. This review aims to briefly describe cough mechanisms, highlight the burden chronic cough can be for the individual, and the clinical impact of chronic cough.

RECENT FINDINGS: Chronic cough is likely caused by different mechanisms in different diseases, which may have therapeutic implications. Chronic cough, in general, has a significant negative effect on quality of life, both with and without a severe comorbid disease. It can lead to social isolation, recurrent depressive episodes, lower work ability, and even conditions such as urinary incontinence. Cough may also be predictive of more frequent exacerbations among patients with COPD, and more rapid lung function decline in idiopathic pulmonary fibrosis. Cough is sometimes reported by patients to be underappreciated by healthcare.

SUMMARY: Chronic cough has a significant negative impact on quality of life, irrespective of diagnosis. Some differences are seen between patients with and without severe disease. Healthcare workers need to pay specific attention to cough, especially patients with severe disease.

PMID:36302225 | DOI:10.1097/SPC.0000000000000623

ERJ Open Res. 2022 Oct 24;8(4):00245-2022. doi: 10.1183/23120541.00245-2022. eCollection 2022 Oct.

ABSTRACT

BACKGROUND: Pirfenidone (PFD) is widely used in patients with idiopathic pulmonary fibrosis (IPF) and its adverse effects, such as nausea and photosensitivity, are well known. Many patients with IPF have reduced doses or even cessation of PFD because of its side-effects. No solutions have been found for these side-effects because the current mechanistic insights are insufficient.

METHODS: Using the results of real-world data analysis from the US Food and Drug Administration Adverse Events Reporting System, we hypothesised that PFD-related symptoms may be similar to pellagra. Reverse translational experiments using female BALB/c mice were performed to validate and estimate this hypothesis. Niacin and its metabolite responses were compared between patients with IPF treated with PFD and those treated without PFD.

RESULTS: The pellagra hypothesis was translated from real-world data analysis. Pharmacological and comprehensive genetic investigations showed that PFD caused pellagra-related nausea and photosensitivity in a mouse model, which may have been mediated by the actions of nicotinamide N-methyltransferase (NNMT). Higher NNMT substrate responses were observed in urine from patients and mice with PFD than in those without PFD.

CONCLUSIONS: PFD may cause pellagra or pellagra-like symptoms such as photosensitivity. Further studies are required to investigate whether niacin prevents pellagra-like symptoms caused by PFD in patients with IPF.

PMID:36299372 | PMC:PMC9589320 | DOI:10.1183/23120541.00245-2022

ERJ Open Res. 2022 Oct 24;8(4):00240-2022. doi: 10.1183/23120541.00240-2022. eCollection 2022 Oct.

ABSTRACT

INTRODUCTION: BI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has antifibrotic properties. Phase I and Ic studies were conducted to investigate the safety, tolerability and pharmacokinetics of BI 1015550 in healthy male subjects and patients with idiopathic pulmonary fibrosis (IPF).

METHODS: In the phase I study, 42 subjects were partially randomised to receive placebo or BI 1015550 in single rising doses of 36 mg and 48 mg, or multiple rising doses of 6 mg and 12 mg twice daily over 14 days. In the phase Ic study, 15 patients with IPF were randomised to receive 18 mg BI 1015550 or placebo twice daily for up to 12 weeks. For both studies, the primary endpoint was the number of subjects with drug-related adverse events (AEs).

RESULTS: In the Phase I study, drug-related AEs were reported for 50.0% of healthy male subjects treated with a single dose of BI 1015550, compared with 16.7% receiving placebo. For those receiving multiple doses, drug-related AEs were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving placebo. The most frequently reported AEs by organ class were nervous system disorders, which were largely driven by headache. In the Phase Ic study, drug-related AEs were reported in 90.0% of patients treated with BI 1015550, compared with 60.0% of those receiving placebo. The most frequent AEs by organ class were gastrointestinal AEs.

CONCLUSIONS: BI 1015550 had an acceptable safety profile in healthy male subjects and male and female patients with IPF, supporting further development in larger trials.

PMID:36299369 | PMC:PMC9589333 | DOI:10.1183/23120541.00240-2022

ERJ Open Res. 2022 Oct 24;8(4):00191-2022. doi: 10.1183/23120541.00191-2022. eCollection 2022 Oct.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic lung condition with poor prognosis. Matrix metalloproteinase-7 (MMP7) is a protein secreted by epithelial cells in IPF lungs. It is not known if MMP7 expression correlates with fibrotic changes in lung tissue.

METHODS: Tissue samples from lung apices and bases were obtained from 20 IPF patients and 14 non-diseased control (NDC) donors. In formalin-fixed paraffin-embedded sections, histological assessment of fibrosis was performed; overall MMP7 positivity was assessed by immunohistochemistry and MMP7+ cells were quantified using multiplex immunohistochemistry. Protein expression of MMP7 in whole lung lysates was quantified by Western blotting. Bulk tissue transcriptomic profiles of 101 samples were analysed using RNA sequencing technologies.

RESULTS: Lung tissue from IPF bases was more fibrotic than in apices. MMP7 protein is elevated in IPF lung base tissue. In IPF whole lung lysates, MMP7 protein levels are increased compared to NDC donors and was increased in IPF lung bases compared to apices. MMP7 protein levels correlated with MMP7 gene expression levels in lung tissue. MMP7 transcript levels were increased in IPF base compared to NDC base lung tissue and increased in IPF base tissue compared to IPF apex tissue.

CONCLUSIONS: Our cross-sectional study suggests that lung epithelial MMP7 expression increases as the tissue becomes more fibrotic and identifies a potentially nonepithelial or immune-cell source. Mechanisms of disease progression in IPF are still unclear, and our study suggests aberrant MMP7 production may be a histological starting point of lung tissue fibrosis.

PMID:36299365 | PMC:PMC9589331 | DOI:10.1183/23120541.00191-2022