Eur Respir J. 2023 May 25;61(5):2300566. doi: 10.1183/13993003.00566-2023. Print 2023 May.

NO ABSTRACT

PMID:37230505 | DOI:10.1183/13993003.00566-2023

Life Sci Alliance. 2023 May 25;6(8):e202201853. doi: 10.26508/lsa.202201853. Print 2023 Aug.

ABSTRACT

Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target the epithelium and human models of fibrotic epithelial damage with suitability for drug discovery are lacking. We developed a model of the aberrant epithelial reprogramming observed in IPF using alveolar organoids derived from human-induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. Deconvolution of RNA-seq data of alveolar organoids indicated that the fibrosis cocktail rapidly increased the proportion of transitional cell types including the KRT5 - /KRT17 + aberrant basaloid phenotype recently identified in the lungs of IPF patients. We found that epithelial reprogramming and extracellular matrix (ECM) production persisted after removal of the fibrosis cocktail. We evaluated the effect of the two clinically approved compounds for IPF, nintedanib and pirfenidone, and found that they reduced the expression of ECM and pro-fibrotic mediators but did not completely reverse epithelial reprogramming. Thus, our system recapitulates key aspects of IPF and is a promising system for drug discovery.

PMID:37230801 | DOI:10.26508/lsa.202201853

Respirol Case Rep. 2023 May 23;11(6):e01160. doi: 10.1002/rcr2.1160. eCollection 2023 Jun.

ABSTRACT

Pulmonary alveolar proteinosis (PAP) affecting transplanted lungs is not well recognized. Herein, we report two cases of PAP after lung transplantation (LTx). The first case was a 4-year-old boy with hereditary pulmonary fibrosis who underwent bilateral LTx and presented with respiratory distress on postoperative day (POD) 23. He was initially treated for acute rejection, died due to infection on POD 248, and was diagnosed with PAP at autopsy. The second case involved a 52-year-old man with idiopathic pulmonary fibrosis who underwent bilateral LTx. On POD 99, chest computed tomography revealed ground-glass opacities. Bronchoalveolar lavage and transbronchial biopsy led to a diagnosis of PAP. Follow-up with immunosuppression tapering resulted in clinical and radiological improvement. PAP after lung transplantation mimics common acute rejection; however, is potentially transient or resolved with tapering immunosuppression, as observed in the second case. Transplant physicians should be aware of this rare complication to avoid misconducting immunosuppressive management.

PMID:37229297 | PMC:PMC10203803 | DOI:10.1002/rcr2.1160

ERJ Open Res. 2023 May 9;9(3):00749-2022. doi: 10.1183/23120541.00749-2022. eCollection 2023 May.

ABSTRACT

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is characterised by upper lobe-dominant fibrosis involving the pleura and subpleural lung parenchyma, with advanced cases often complicated by progressive weight loss. Therefore, we hypothesised that nutritional status is associated with mortality in IPPFE.

METHODS: This retrospective study assesses nutritional status at the time of diagnosis and 1 year after diagnosis in 131 patients with IPPFE. Malnutrition-related risk was evaluated using the Geriatric Nutritional Risk Index (GNRI).

RESULTS: Of the 131 patients, 96 (73.8%) were at malnutrition-related risk at the time of diagnosis according to the GNRI. Of these, 21 patients (16.0%) were classified as at major malnutrition-related risk (GNRI <82). Patients at major malnutrition-related risk were significantly older and had worse pulmonary function than patients at low (GNRI 92- <98) and moderate (GNRI 82- <92) malnutrition-related risk. GNRI scores decreased significantly from the time of diagnosis to 1 year after diagnosis. Patients with a lower GNRI (<91.8) had significantly shorter survival than patients with a median GNRI or higher (≥91.8). Patients with declines in annual GNRI scores of ≥5 had significantly shorter survival than patients with declines in annual GNRI scores of <5. In multivariate analysis, major malnutrition-related risk was significantly associated with increased mortality after adjustment for age, sex and forced vital capacity (hazard ratio 1.957). A composite scoring model including age, sex and major malnutrition-related risk was able to separate mortality risk in IPPFE.

CONCLUSION: Assessment of nutritional status by the GNRI provides useful information for managing patients with IPPFE by predicting mortality risk.

PMID:37228291 | PMC:PMC10204813 | DOI:10.1183/23120541.00749-2022

ERJ Open Res. 2023 May 22;9(3):00720-2022. doi: 10.1183/23120541.00720-2022. eCollection 2023 May.

ABSTRACT

BACKGROUND: High bacterial burden in the lung microbiota predicts progression of idiopathic pulmonary fibrosis (IPF). Azithromycin (AZT) is a macrolide antibiotic known to alter the lung microbiota in several chronic pulmonary diseases, and observational studies have shown a positive effect of AZT on mortality and hospitalisation rate in IPF. However, the effect of AZT on the lung microbiota in IPF remains unknown.

METHODS: We sought to determine the impact of a 3-month course of AZT on the lung microbiota in IPF. We assessed sputum and oropharyngeal swab specimens from 24 adults with IPF included in a randomised controlled crossover trial of oral AZT 500 mg 3 times per week. 16S rRNA gene amplicon sequencing and quantitative PCR (qPCR) were performed to assess bacterial communities. Antibiotic resistance genes (ARGs) were assessed using real-time qPCR.

RESULTS: AZT significantly decreased community diversity with a stronger and more persistent effect in the lower airways (sputum). AZT treatment altered the temporal kinetics of the upper (oropharyngeal swab) and lower airway microbiota, increasing community similarity between the two sites for 1 month after macrolide cessation. Patients with an increase in ARG carriage had lower bacterial density and enrichment of the genus Streptococcus. In contrast, patients with more stable ARG carriage had higher bacterial density and enrichment in Prevotella.

CONCLUSIONS: AZT caused sustained changes in the diversity and composition of the upper and lower airway microbiota in IPF, with effects on the temporal and spatial dynamics between the two sites.

PMID:37228285 | PMC:PMC10204823 | DOI:10.1183/23120541.00720-2022

ERJ Open Res. 2023 May 22;9(3):00585-2022. doi: 10.1183/23120541.00585-2022. eCollection 2023 May.

ABSTRACT

BACKGROUND: Pulmonary rehabilitation improves mood disorder in COPD, but there are limited data in idiopathic pulmonary fibrosis (IPF). The aims of this cohort study were to investigate whether pulmonary rehabilitation reduces mood disorder in IPF, and estimate the minimal important difference (MID) of the Hospital Anxiety and Depression Scale (HADS).

METHODS: HADS and core pulmonary rehabilitation outcomes were measured in 166 participants before and after an 8-week, in-person, outpatient pulmonary rehabilitation programme. Anchor- and distribution-based methods were used to calculate the MID of HADS-Anxiety (A) and HADS-Depression (D).

RESULTS: Suggestive or probable anxiety and depression (HADS ≥8) were present in 35% and 37% of participants, respectively, at baseline, and this reduced significantly following pulmonary rehabilitation (post-pulmonary rehabilitation: HADS-A 23%, HADS-D 26%). Overall, there was a significant reduction in HADS-D (mean change -1.1, 95% CI -1.6- -0.5), but not HADS-A (-0.6, -1.3-0.15) with pulmonary rehabilitation. Subgroup analysis of those with HADS ≥8 revealed significant improvements in HADS domains (mean change: HADS-A -4.5, 95% CI -5.7- -3.4; median change: HADS-D -4.0, interquartile range -6.0- -1.0). The mean (range) MID estimates for HADS-A and HADS-D were -2 (-2.3- -1.7) and -1.2 (-1.9- -0.5), respectively.

CONCLUSION: In people with IPF and suggestive or probable mood disorder, pulmonary rehabilitation reduces anxiety and depression.

PMID:37228278 | PMC:PMC10204825 | DOI:10.1183/23120541.00585-2022

ERJ Open Res. 2023 May 22;9(3):00679-2022. doi: 10.1183/23120541.00679-2022. eCollection 2023 May.

ABSTRACT

BACKGROUND: Interleukin-11 (IL-11) is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. In IPF there is disrupted alveolar structural architecture, yet the effect of IL-11 on the dysregulated alveolar repair remains to be elucidated.

METHODS: We hypothesised that epithelial-fibroblast communication associated with lung repair is disrupted by IL-11. Thus, we studied whether IL-11 affects the repair responses of alveolar lung epithelium using mouse lung organoids and precision-cut lung slices (PCLS). Additionally, we assessed the anatomical distribution of IL-11 and IL-11 receptor (IL-11R) in human control and IPF lungs using immunohistochemistry.

RESULTS: IL-11 protein was observed in airway epithelium, macrophages and in IPF lungs, also in areas of alveolar type 2 (AT2) cell hyperplasia. IL-11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid co-cultures of epithelial cells with lung fibroblasts, IL-11 decreased organoid number and reduced the fraction of Prosurfactant Protein C-expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS exposed to IL-11, ciliated cell markers were increased. The response of primary human fibroblasts to IL-11 on gene expression level was minimal, though bulk RNA-sequencing revealed IL-11 modulated various processes which are associated with IPF, including unfolded protein response, glycolysis and Notch signalling.

CONCLUSIONS: IL-11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. Evidence for a contribution of dysregulated fibroblast-epithelial communication to this process is limited.

PMID:37228276 | PMC:PMC10204861 | DOI:10.1183/23120541.00679-2022

ERJ Open Res. 2023 May 9;9(3):00124-2023. doi: 10.1183/23120541.00124-2023. eCollection 2023 May.

ABSTRACT

BACKGROUND: The Distance-Oxygen-Gender-Age-Physiology (DO-GAP) index has been shown to improve prognostication in idiopathic pulmonary fibrosis (IPF) compared to the Gender-Age-Physiology (GAP) score. We sought to externally validate the DO-GAP index compared to the GAP index for baseline risk assessment in patients with IPF. Additionally, we evaluated the utility of serial change in the DO-GAP index in predicting survival.

METHODS: We performed an analysis of patients with IPF from the Pulmonary Fibrosis Foundation-Patient Registry (PFF-PR). Discrimination and calibration of the two models were assessed to predict transplant-free survival and IPF-related mortality. Joint longitudinal time-to-event modelling was utilised to individualise survival prediction based on DO-GAP index trajectory.

RESULTS: There were 516 patients with IPF from the PFF-PR with available demographics, pulmonary function tests, 6-min walk test data and outcomes included in this analysis. The DO-GAP index (C-statistic: 0.73) demonstrated improved discrimination in discerning transplant-free survival compared to the GAP index (C-statistic: 0.67). DO-GAP index calibration was adequate, and the model retained predictive accuracy to identify IPF-related mortality (C-statistic: 0.74). The DO-GAP index was similarly accurate in the subset of patients taking antifibrotic medications. Serial change in the DO-GAP index improved model discrimination (cross-validated area under the curve: 0.83) enabling the personalised prediction of disease trajectory in individual patients.

CONCLUSION: The DO-GAP index is a simple, validated, multidimensional score that accurately predicts transplant-free survival in patients with IPF and can be adapted longitudinally in individual patients. The DO-GAP may also find use in studies of IPF to risk stratify patients and possibly as a clinical trial end-point.

PMID:37228268 | PMC:PMC10204731 | DOI:10.1183/23120541.00124-2023

Arch Pathol Lab Med. 2023 May 23. doi: 10.5858/arpa.2022-0530-OA. Online ahead of print.

ABSTRACT

CONTEXT.—: The pathologic diagnosis of usual interstitial pneumonia (UIP) remains a challenging area, and application of histologic UIP guidelines has proved difficult.

OBJECTIVE.—: To understand current practice approaches by pulmonary pathologists for the histologic diagnosis of UIP and other fibrotic interstitial lung diseases (ILDs).

DESIGN.—: The Pulmonary Pathology Society (PPS) ILD Working Group developed and sent a 5-part survey on fibrotic ILD electronically to the PPS membership.

RESULTS.—: One hundred sixty-one completed surveys were analyzed. Of the respondents, 89% reported using published histologic features in clinical guidelines for idiopathic pulmonary fibrosis (IPF) in their pathologic diagnosis; however, there was variability in reporting terminology, quantity and quality of histologic features, and the use of guideline categorization. Respondents were very likely to have access to pulmonary pathology colleagues (79%), pulmonologists (98%), and radiologists (94%) to discuss cases. Half of respondents reported they may alter their pathologic diagnosis based on additional clinical and radiologic history if it is pertinent. Airway-centered fibrosis, granulomas, and types of inflammatory infiltrates were considered important, but there was poor agreement on how these features are defined.

CONCLUSIONS.—: There is significant consensus among the PPS membership on the importance of histologic guidelines/features of UIP. There are unmet needs for (1) consensus and standardization of diagnostic terminology and incorporation of recommended histopathologic categories from the clinical IPF guidelines into pathology reports, (2) agreement on how to incorporate into the report relevant clinical and radiographic information, and (3) defining the quantity and quality of features needed to suggest alternative diagnoses.

PMID:37226833 | DOI:10.5858/arpa.2022-0530-OA

Eur J Pharm Biopharm. 2023 May 22:S0939-6411(23)00139-X. doi: 10.1016/j.ejpb.2023.05.017. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and often fatal lung disease caused by multiple factors. Currently, safe, and effective drugs for the treatment of IPF have been extremely scarce. Baicalin (BA) is used to treat pulmonary fibrosis, IPF, chronic obstructive pulmonary disease, and other lung diseases. Ambroxol hydrochloride (AH), a respiratory tract lubricant and expectorant, is often used to treat chronic respiratory diseases, such as bronchial asthma, emphysema, tuberculosis, and cough. The combination of BA and AH can relieve cough and phlegm, improve lung function, and potentially treat IPF and its symptoms. However, given the extremely low solubility of BA, its bioavailability for oral absorptions is also low. AH, on the other hand, has been associated with certain side effects, such as gastrointestinal tract and acute allergic reactions, which limit its applicability. Therefore, an efficient drug delivery system is urgently needed to address the mentioned problems. This study combined BA and AH as model drugs with L-leucine (L-leu) as the excipient to prepare BA/AH dry powder inhalations (BA/AH DPIs) using the co-spray drying method. We the performed modern pharmaceutical evaluation, which includes particle size, differential scanning calorimetry analysis, X-ray diffraction, scanning electron microscope, hygroscopicity, in vitro aerodynamic analysis, pharmacokinetics, and pharmacodynamics. Notably, BA/AH DPIs were found to be advantageous over BA and AH in treating IPF and had better efficacy in improving lung function than did the positive drug pirfenidone. The BA/AH DPI is a promising preparation for the treatment of IPF given its lung targeting, rapid efficacy, and high lung bioavailability.

PMID:37224929 | DOI:10.1016/j.ejpb.2023.05.017

Intern Med. 2023 May 24. doi: 10.2169/internalmedicine.1663-23. Online ahead of print.

ABSTRACT

A 48-year-old woman was admitted to our hospital with acute respiratory failure. Chest computed tomography showed ground-glass opacity and patchy emphysematous lesions in both lungs. Corticosteroid therapy was effective; however, the disease worsened with the tapering of corticosteroids. Bronchoalveolar lavage revealed hemosiderin-laden macrophages, and video-assisted thoracic surgery showed diffuse interstitial fibrosis with diffuse alveolar hemorrhage (DAH). There was no evidence of vasculitis nor autoimmune diseases. This patient was diagnosed with idiopathic pulmonary hemosiderosis (IPH) that progressed to end-stage pulmonary fibrosis despite treatment. Autopsy demonstrated DAH with pulmonary fibrosis and emphysematous change, suggesting IPH-related pulmonary lesions.

PMID:37225487 | DOI:10.2169/internalmedicine.1663-23

Ann Hum Genet. 2023 May 23. doi: 10.1111/ahg.12509. Online ahead of print.

ABSTRACT

Aggregate tests of rare variants are often employed to identify associated regions compared to sequentially testing each individual variant. When an aggregate test is significant, it is of interest to identify which rare variants are "driving" the association. We recently developed the rare variant influential filtering tool (RIFT) to identify influential rare variants and showed RIFT had higher true positive rates compared to other published methods. Here we use importance measures from the standard random forest (RF) and variable importance weighted RF (vi-RF) to identify influential variants. For very rare variants (minor allele frequency [MAF] < 0.001), the vi-RF:Accuracy method had the highest median true positive rate (TPR = 0.24; interquartile range [IQR]: 0.13, 0.42) followed by the RF:Accuracy method (TPR = 0.16; IQR: 0.07, 0.33) and both were superior to RIFT (TPR = 0.05; IQR: 0.02, 0.15). Among uncommon variants (0.001 < MAF < 0.03), the RF methods had higher true positive rates than RIFT while observing comparable false positive rates. Finally, we applied the RF methods to a targeted resequencing study in idiopathic pulmonary fibrosis (IPF), in which the vi-RF approach identified eight and seven variants in TERT and FAM13A, respectively. In summary, the vi-RF provides an improved, objective approach to identifying influential variants following a significant aggregate test. We have expanded our previously developed R package RIFT to include the random forest methods.

PMID:37221924 | DOI:10.1111/ahg.12509

BMC Pulm Med. 2023 May 23;23(1):179. doi: 10.1186/s12890-023-02476-7.

ABSTRACT

BACKGROUND: Most patients with idiopathic pulmonary fibrosis (IPF) complain of cough. IPF-associated cough is widely characterized as dry or non-productive. The aim of this study was to compare chronic cough in early stage IPF patients to cough in subjects with chronic cough from a community-based sample and, especially, to investigate whether cough in IPF is less productive than chronic cough in a community-based sample.

METHODS: The IPF cough population consisted of 46 biopsy-confirmed patients who complained of chronic cough. Control population consisted of subjects with chronic cough, gathered by a community-based email survey sent to public service employees and the Finnish Pensioners' Federation. A case-control setting was applied by having four age, gender, and smoking-status matched subjects from the community sample for each IPF cough patient. A cough specific quality of life questionnaire (Leicester Cough Questionnaire (LCQ)) was filled in by all subjects. The LCQ questionnaire contains 19 questions, each question is scored from 1 to 7 and total score from 3 to 21 with a smaller value indicating more severe impairment.

RESULTS: The sputum production frequency, as assessed by LCQ question 2, was 5.0 (3.0-6.0) in the IPF chronic cough population and 5.0 (3.0-6.0) in the community-based chronic cough population (median and interquartile range p= 0.72). The LCQ total score was 14.8 (11.5-18.1) in the IPF chronic cough population and 15.4 (13.0-17.5) in the community-based chronic cough population (p=0.76). The domain impact scores were physical, 4.9 (3.9-6.1) vs. 5.1 (4.5-5.6) (p=0.80); psychological, 4.6 (3.7-5.9) vs. 4.7 (3.9-5.7) (p=0.90); and social, 5.5 (3.7-6.5) vs. 5.5 (4.5-6.3) (p=0.84), respectively. Furthermore, cough response to paint or fumes, cough disturbing sleep, and cough frequency per day did not differ between the groups.

CONCLUSION: Cough in early stage IPF patients was not distinguishable from chronic cough in the community-based population by LCQ. Especially, there was no difference in the self-reported frequency of cough-associated sputum production.

PMID:37221535 | DOI:10.1186/s12890-023-02476-7

Respirology. 2023 May 23. doi: 10.1111/resp.14523. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung fibrosis of unknown aetiology. Epidemiological studies have suggested that IPF progression may negatively affect nutritional status. Weight loss during antifibrotic therapy is also frequently encountered. The association of nutritional status and outcome has not been fully evaluated in IPF patients.

METHODS: This retrospective multicohort study assessed nutritional status of 301 IPF patients receiving antifibrotic therapy (Hamamatsu cohort, n = 151; Seirei cohort, n = 150). Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI). The GNRI was calculated based on body mass index and serum albumin. The relationship between nutritional status and tolerability of antifibrotic therapy as well as mortality was explored.

RESULTS: Of 301 patients, 113 (37.5%) had malnutrition-related risk (GNRI < 98). Patients with malnutrition-related risk were older, had increased exacerbations and worse pulmonary function than those without a GNRI status <98. Malnutrition-related risk was associated with a higher incidence of discontinuation of antifibrotic therapy, particulary due to gastrointestinal disturbances. IPF patients with malnutrition-related risk (GNRI < 98) had shorter survival than those without such risk (median survival: 25.9 vs. 41.1 months, p < 0.001). In multivariate analysis, malnutrition-related risk was a prognostic indicator of antifibrotic therapy discontinuation and mortality, independent of age, sex, forced vital capacity, or gender-age-physiology index.

CONCLUSION: Nutritional status has significant effects on the treatment and outcome in patients with IPF. Assessment of nutritional status may provide important information for managing patients with IPF.

PMID:37221050 | DOI:10.1111/resp.14523

Thorax. 2023 May 22:thorax-2023-220012. doi: 10.1136/thorax-2023-220012. Online ahead of print.

ABSTRACT

Smoking has been considered a risk factor for idiopathic pulmonary fibrosis (IPF) in observational studies. To assess whether smoking plays a causal role in IPF, we performed a Mendelian randomization study using genetic association data of 10 382 cases with IPF and 968 080 controls. We found that genetic predisposition to smoking initiation (based on 378 variants) and lifetime smoking (based on 126 variants) were associated with a higher risk of IPF. Our study suggests a potential causal effect of smoking on increasing IPF risk from a genetic perspective.

PMID:37217291 | DOI:10.1136/thorax-2023-220012

Mater Today Bio. 2023 May 2;20:100653. doi: 10.1016/j.mtbio.2023.100653. eCollection 2023 Jun.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease with poor prognosis and high mortality rate. In the process of IPF, inflammatory dysregulation of macrophages and massive fibroblast aggregation and proliferation destroy alveoli, which cause pulmonary dysfunction, and ultimately lead to death due to respiratory failure. In the treatment of IPF, crossing biological barriers and delivering drugs to lung interstitium are the major challenges. In order to avoid the side effect of macrophages proliferation, we proposed, designed, and evaluated the strategy which combined macrophage depletion by intervaginal space injection and intravenous targeted therapy on bleomycin mouse model. We found that it inhibited pulmonary macrophages, reduced macrophage depletion in non-target organs, improved pulmonary drug targeting, impeded the progression of pulmonary fibrosis, and accelerated the recovery of pulmonary function. This combination therapeutic strategy shows good biosafety and efficacy, induces a targeted response, and is promising as a practical new clinical approach towards the treatment of pulmonary fibrosis.

PMID:37214554 | PMC:PMC10192919 | DOI:10.1016/j.mtbio.2023.100653

Open Access Rheumatol. 2023 May 15;15:65-79. doi: 10.2147/OARRR.S318826. eCollection 2023.

ABSTRACT

Complement system (CS) dysregulation is a key factor in the pathogenesis of different autoimmune diseases playing a central role in many immune innate and adaptive processes. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by ta breach of self-tolerance leading to a synovitis and extra-articular manifestations. The CS is activated in RA and seems not only to mediate direct tissue damage but also play a role in the initiation of RA pathogenetic mechanisms through interactions with citrullinated proteins. Interstitial lung disease (ILD) represents the most common extra-articular manifestation that can lead to progressive fibrosis. In this review, we focused on the evidence of CS dysregulation in RA and in ILD, and highlighted the role of the CS in both the innate and adaptive immune responses in the development of diseases, by using idiopathic pulmonary fibrosis as a model of lung disease. As a proof of concept, we dissected the evidence that several treatments used to treat RA and ILD such as glucocorticoids, pirfenidone, disease modifying antirheumatic drugs, targeted biologics such as tumor necrosis factor (TNF)-inhibitors, rituximab, tocilizumab, and nintedanib may act indirectly on the CS, suggesting that the CS might represent a potential therapeutic target in these complex diseases.

PMID:37214353 | PMC:PMC10198272 | DOI:10.2147/OARRR.S318826

J Vis Exp. 2023 May 5;(195). doi: 10.3791/64742.

ABSTRACT

The inflammatory response caused by early lung injury is one of the important causes of the development of idiopathic pulmonary fibrosis (IPF), which is accompanied by the activation of inflammatory cells such as macrophages and neutrophils, as well as the release of inflammatory factors including TNF-α, IL-1β, and IL-6. Early inflammation caused by activated pulmonary interstitial macrophages (IMs) in response to IL-33 stimulation is known to play a vital role in the pathological process of IPF. This protocol describes the adoptive transfer of IMs stimulated by IL-33 into the lungs of mice to study IPF development. It involves the isolation and culture of primary IMs from host mouse lungs, followed by the adoptive transfer of stimulated IMs into the alveoli of bleomycin (BLM)-induced IPF recipient mice (which have been previously depleted of alveolar macrophages by treatment with clodronate liposomes), and the pathological evaluation of those mice. The representative results show that the adoptive transfer of IL-33-stimulated macrophages aggravates pulmonary fibrosis in mice, suggesting that the establishment of the macrophage adoptive transfer experiment is a good technical means to study IPF pathology.

PMID:37212557 | DOI:10.3791/64742

EMBO Mol Med. 2023 May 22:e16940. doi: 10.15252/emmm.202216940. Online ahead of print.

ABSTRACT

Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.

PMID:37212275 | DOI:10.15252/emmm.202216940

Pulm Ther. 2023 May 20. doi: 10.1007/s41030-023-00226-y. Online ahead of print.

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) usually suffer from post-acute sequelae of coronavirus disease 2019 (PASC). Pulmonary fibrosis (PF) has the most significant long-term impact on patients' respiratory health, called post-COVID-19 pulmonary fibrosis (PC19-PF). PC19- PF can be caused by acute respiratory distress syndrome (ARDS) or pneumonia due to COVID-19. The risk factors of PC19-PF, such as older age, chronic comorbidities, the use of mechanical ventilation during the acute phase, and female sex, should be considered. Individuals with COVID-19 pneumonia symptoms lasting at least 12 weeks following diagnosis, including cough, dyspnea, exertional dyspnea, and poor saturation, accounted for nearly all disease occurrences. PC19-PF is characterized by persistent fibrotic tomographic sequelae associated with functional impairment throughout follow-up. Thus, clinical examination, radiology, pulmonary function tests, and pathological findings should be done to diagnose PC19-PF patients. PFT indicated persistent limitations in diffusion capacity and restrictive physiology, despite the absence of previous testing and inconsistency in the timeliness of assessments following acute illness. It has been hypothesized that PC19-PF patients may benefit from idiopathic pulmonary fibrosis treatment to prevent continued infection-related disorders, enhance the healing phase, and manage fibroproliferative processes. Immunomodulatory agents might reduce inflammation and the length of mechanical ventilation during the acute phase of COVID-19 infection, and the risk of the PC19-PF stage. Pulmonary rehabilitation, incorporating exercise training, physical education, and behavioral modifications, can improve the physical and psychological conditions of patients with PC19-PF.

PMID:37209374 | DOI:10.1007/s41030-023-00226-y