Respir Med Case Rep. 2022 Aug 19;39:101729. doi: 10.1016/j.rmcr.2022.101729. eCollection 2022.

ABSTRACT

A 32-year-old man who had worked as a welder for 13 years was hospitalized for a fever and hemosputum with dyspnea. He was diagnosed with welding fume-associated lung disease with alveolar hemorrhaging and acute respiratory failure. Despite surviving the acute phase with corticosteroid therapy, hypoxemia persisted after a month and a half, requiring home oxygen therapy. As a result of the introduction of nintedanib, his clinical findings gradually improved, and the patient was weaned from oxygen therapy after six months. Inhalation of a large amount of welding fumes in a short period can cause alveolar hemorrhaging and prolonged pulmonary dysfunction.

PMID:36060640 | PMC:PMC9428916 | DOI:10.1016/j.rmcr.2022.101729

Front Pharmacol. 2022 Aug 17;13:837680. doi: 10.3389/fphar.2022.837680. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality and morbidity. Approval of antifibrotic therapy has ameliorated disease progression, but therapy response is heterogeneous and to date, adequate biomarkers predicting therapy response are lacking. In recent years metabolomic technology has improved and is broadly applied in cancer research thus enabling its use in other fields. Recently both aberrant metabolic and lipidomic pathways have been described to influence profibrotic responses. We thus aimed to characterize the metabolomic and lipidomic changes between IPF and healthy volunteers (HV) and analyze metabolomic changes following treatment with nintedanib and pirfenidone. We collected serial serum samples from two IPF cohorts from Germany (n = 122) and Spain (n = 21) and additionally age-matched healthy volunteers (n = 16). Metabolomic analysis of 630 metabolites covering 14 small molecule and 12 different lipid classes was carried out using flow injection analysis tandem mass spectrometry for lipids and liquid chromatography tandem mass spectrometry for small molecules. Levels were correlated with survival and disease severity. We identified 109 deregulated analytes in IPF compared to HV in cohort 1 and 112 deregulated analytes in cohort 2. Metabolites which were up-regulated in both cohorts were mainly triglycerides while the main class of down-regulated metabolites were phosphatidylcholines. Only a minority of de-regulated analytes were small molecules. Triglyceride subclasses were inversely correlated with baseline disease severity (GAP-score) and a clinical compound endpoint of lung function decline or death. No changes in the metabolic profiles were observed following treatment with pirfenidone. Nintedanib treatment induced up-regulation of triglycerides and phosphatidylcholines. Patients in whom an increase in these metabolites was observed showed a trend towards better survival using the 2-years composite endpoint (HR 2.46, p = 0.06). In conclusion, we report major changes in metabolites in two independent cohorts testing a large number of patients. Specific lipidic metabolite signatures may serve as biomarkers for disease progression or favorable treatment response to nintedanib.

PMID:36059968 | PMC:PMC9428132 | DOI:10.3389/fphar.2022.837680

Respir Res. 2022 Sep 3;23(1):228. doi: 10.1186/s12931-022-02159-7.

ABSTRACT

BACKGROUND: Sarcopenia gained importance in the evaluation of patients with chronic respiratory diseases, including idiopathic pulmonary fibrosis (IPF), since it may impact negatively on clinical outcomes.

AIM: Aim of this study is to evaluate the prevalence and factors associated with sarcopenia, defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) 2019 definition, and to evaluate the prevalence of the single criteria that define the EWGSOP2 definition (muscle strength, muscle quantity and physical performance), in a cohort of consecutive patients with IPF prospectively followed up in 9 hospitals in Northern Italy between December 2018 and May 2021.

METHODS: Enrolled patients underwent an extensive pulmonary and nutritional assessment, including bioelectrical impedance analysis, dynamometry and 4-m gait speed test, both at IPF diagnosis and at 6-month follow-up.

RESULTS: Out of the 83 patients (81% males, mean age 72.5 years) with IPF at disease diagnosis enrolled in the study, 19 (22.9%) showed sarcopenia, including 2 (2.4%) with severe sarcopenia, 5 (6.0%) with confirmed sarcopenia and 12 (14.5%) with probable sarcopenia. Sarcopenia was associated with a significantly higher severity of the disease and sedentary lifestyle, while no differences were observed in regards to body mass index, history of weight loss and comorbidities between patients with and without sarcopenia. Out of the 64 patients without sarcopenia at baseline, 16 cases showed alteration of muscle quantity and/or physical performance. In the 51 patients with complete data at 6-month follow-up, there were no cases of severe sarcopenia, 1 case (2.0%) showed confirmed sarcopenia, while the prevalence of probable sarcopenia was 19.6% (10 cases). No differences in regards to antifibrotic treatment received and onset of gastrointestinal side effects were observed between patients with and without sarcopenia at follow-up.

CONCLUSIONS: The prevalence of sarcopenia in patients with IPF both at diagnosis and at 6-month follow-up was low but not negligible and was associated with higher severity of the disease and sedentary lifestyle. In IPF patients, a comprehensive diagnostic work-up including all the criteria defining the EWGSOP2 definition might be more useful than a series testing for prompt recognition of nutritional and physical performance abnormalities.

PMID:36057620 | DOI:10.1186/s12931-022-02159-7

Trials. 2022 Sep 2;23(1):725. doi: 10.1186/s13063-022-06684-0.

ABSTRACT

BACKGROUND AND RATIONALE: Idiopathic pulmonary fibrosis is a critical disease with a poor prognosis. Although different studies have been conducted for the treatment of idiopathic pulmonary fibrosis, limited treatments are available. Jin-shui Huan-xian granule (JHG), which is a Chinese medicine herbal compound, has shown promising efficacy in reducing frequencies of acute exacerbations, improving exercise capacity the quality of life of patients with idiopathic pulmonary fibrosis. This study is to evaluate the efficacy and safety of JHG for IPF.

SUBJECTS AND METHODS: This is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 312 idiopathic pulmonary fibrosis patients will be enrolled and randomly allocated to one of the two groups with 1:1. After a 2-week washout period, 52-week treatment will also be performed for all the patients. Patients in the experimental group and the control group will be given JHG and JHG placebo, respectively. Outcome measures including acute exacerbations, pulmonary function, dyspnea, exercise capacity, and quality of life will be evaluated in this study.

DISCUSSION: Based on our previous study, it is hypothesized that JHG will reduce acute exacerbations; improve exercise capacity, pulmonary function, and quality of life; and delay the disease progression-free. High-level evidence-based support for TCM in IPF will also be obtained in this study.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04187690. Register on December 11, 2019.

PMID:36056382 | DOI:10.1186/s13063-022-06684-0

Respirology. 2022 Aug 28. doi: 10.1111/resp.14352. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Antifibrotic drugs are the standard treatments for patients with idiopathic pulmonary fibrosis (IPF). This study aims to assess the safety of antifibrotic treatment in IPF patients undergoing lung transplantation.

METHODS: Patients with a diagnosis of IPF who received a lung transplant between January 2015 and June 2019 at four Spanish hospitals specialized in lung transplantation were retrospectively recruited. Cases were defined as patients receiving antifibrotic treatments at time of transplant. Each case was matched with a control who did not receive antifibrotic treatment.

RESULTS: A total of 164 patients were included in the study cohort (103 cases and 61 controls). There were no statistically significant differences between the cases and controls in any of the items studied related to transplantation except the time until the appearance of chest wall dehiscence: although there were no differences in the incidence of wall dehiscence in either group (12.3% vs. 13.7%; p = 0.318), the patients on antifibrotic drugs experienced it earlier (21 days [IQR = 12.5-41.5] vs. 63 days [IQR = 46.75-152.25]; p = 0.012). There were no differences in overall post-transplant survival between the two groups (p = 0.698) or in conditional survival at 30 days, 90 days, 3 years or 5 years. However, 1 year survival was significantly greater among controls (80.6% vs. 93.3%; p = 0.028).

CONCLUSION: There was evidence that chest wall dehiscences appeared earlier post-transplant in patients using antifibrotics, even though this factor did not significantly impact survival.

PMID:36053911 | DOI:10.1111/resp.14352

Ther Adv Chronic Dis. 2022 Aug 22;13:20406223221117982. doi: 10.1177/20406223221117982. eCollection 2022.

ABSTRACT

BACKGROUND: Pirfenidone and nintedanib are considered as the standard of care in idiopathic pulmonary fibrosis (IPF), but there is no consensus as to which of these two agents should be regarded as first-line treatment.

OBJECTIVE: To provide real-world data on therapeutic decisions of pulmonary specialists, particularly the choice of the antifibrotic drug in patients with IPF.

METHODS: This was a multicenter, prospective survey collecting clinical data of patients with IPF considered as candidates for antifibrotic treatment between September 2019 and December 2020. Clinical characteristics and information on the therapeutic approach were retrieved. Statistical evaluation included multiple logistic regression analysis with stepwise model selection.

RESULTS: Data on 188 patients [74.5% male, median age 73 (interquartile range, 68-78) years] considered for antifibrotic therapy were collected. Treatment was initiated in 138 patients, while 50 patients did not receive an antifibrotic, mainly due to the lack of consent for treatment and IPF severity. Seventy-two patients received pirfenidone and 66 received nintedanib. Dosing protocol (p < 0.01) and patient preference (p = 0.049) were more frequently associated with the choice of nintedanib, while comorbidity profile (p = 0.0003) and concomitant medication use (p = 0.03) were more frequently associated with the choice of pirfenidone. Age (p = 0.002), lung transfer factor for carbon monoxide (TLCO) (p = 0.001), and gastrointestinal bleeding (p = 0.03) were significantly associated with the qualification for the antifibrotic treatment.

CONCLUSION: This real-world prospective study showed that dose protocol and patient preference were more frequently associated with the choice of nintedanib, while the comorbidity profile and concomitant medication use were more frequently associated with the choice of pirfenidone. Age, TLCO, and history of gastrointestinal bleeding were significant factors influencing the decision to initiate antifibrotic therapy.

PMID:36052286 | PMC:PMC9425901 | DOI:10.1177/20406223221117982

J Investig Med High Impact Case Rep. 2022 Jan-Dec;10:23247096221121403. doi: 10.1177/23247096221121403.

ABSTRACT

Dermatomyositis sine dermatitis (DMSD) is one of the rare idiopathic inflammatory myopathies. Based on predominant symptoms faced by patients, it is classified into 3 types: (1) classic dermatomyositis (DM), where patients have both muscle and skin symptoms; and (2) amyopathic DM, when only skin symptoms present with no muscle involvement. Whereas (3) DMSD has mainly muscle symptoms with muscle antibodies but no skin rashes. There have been only nearly 10 published articles about DMSD proving this disease's scarcity. At the same time, it shows the importance of discussing the unusual presentation of such a rare disease. Here we present, a 28-year-old woman with worsening proximal muscle weakness. The decreased muscle strength on physical examination and elevated creatinine kinase required more work up for autoimmune disease. Interestingly, on muscle biopsy, anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody returned positive, and the patient responded well to 3 days course of steroids. The lack of skin involvement, the predominance of muscle symptoms, and positive anti-MDA5 antibody indispensably diagnosed patients with DMSD. The previously published articles have proved the association between anti-NXP-2 antibody and DMSD, which was not seen in our case. The systemic involvement of DMSD can lead to interstitial lung disease, where due to diffuse alveolar damage and pulmonary fibrosis, patients end up requiring intubation and may be associated with higher-level mortality. In our case, chest X-rays and computed tomography (CT) scans were unremarkable for lung involvement, so as no paraneoplastic syndromes were present, which has also been reported in DMSD patients previously.

PMID:36050930 | DOI:10.1177/23247096221121403

PLoS One. 2022 Sep 1;17(9):e0273854. doi: 10.1371/journal.pone.0273854. eCollection 2022.

ABSTRACT

BACKGROUND: There is no clear evidence whether pirfenidone has a benefit in patients with probable or possible UIP, i.e. when idiopathic pulmonary fibrosis (IPF) is diagnosed with a lower degree of diagnostic certainty. We report on outcomes of treatment with pirfenidone in IPF patients diagnosed with various degrees of certainty.

METHODS AND FINDINGS: We followed patients in the multi-national European MultiPartner IPF Registry (EMPIRE) first seen between 2015 and 2018. Patients were assessed with HRCT, histopathology and received a multi-disciplinary team (MDT) IPF diagnosis. Endpoints of interest were overall survival (OS), progression-free survival (PFS) and lung function decline.

RESULTS: A total of 1626 patients were analysed, treated with either pirfenidone (N = 808) or receiving no antifibrotic treatment (N = 818). When patients treated with pirfenidone were compared to patients not receiving antifibrotic treatment, OS (one-, two- and three-year probability of survival 0.871 vs 0.798; 0.728 vs 0.632; 0.579 vs 0.556, P = 0.002), and PFS (one-, two- and three-year probability of survival 0.597 vs 0.536; 0.309 vs 0.281; 0.158 vs 0.148, P = 0.043) was higher, and FVC decline smaller (-0.073 l/yr vs -0.169 l/yr, P = 0.017). The benefit of pirfenidone on OS and PFS was also seen in patients with probable or possible IPF.

CONCLUSIONS: This EMPIRE analysis confirms the favourable outcomes observed for pirfenidone treatment in patients with definitive IPF and indicates benefits also for patients with probable or possible IPF.

PMID:36048805 | DOI:10.1371/journal.pone.0273854

Am J Respir Crit Care Med. 2022 Sep 1. doi: 10.1164/rccm.202105-1284OC. Online ahead of print.

ABSTRACT

RATIONALE: Although alveolar epithelial cells type II (AEC2) are chronically injured in Idiopathic Pulmonary Fibrosis (IPF), they contribute to epithelial regeneration in IPF.

OBJECTIVES: We hypothezised that Notch signaling may contribute to AEC2 proliferation, de-differentiation characterized by loss of surfactant processing machinery and lung fibrosis in IPF Methods: We applied microarray analysis, kinome profiling, flow cytometry, immunofluorescence analysis, western blotting, qPCR, proliferation- and surface activity- analysis to study epithelial differentiation, proliferation and matrix deposition in vitro (AEC2 cell lines, primary murine/human AEC2), ex vivo (human IPF-derived precision cut lung slices; IPF-PCLS) and in vivo (bleomycin-, pepstatin-application, Notch1 ICD overexpression) Measurements and Main Results: We document here extensive surfactant protein (SP)-B/C processing defects in IPF AEC2, due to loss of Napsin A, resulting in increased intra-alveolar surface tension and alveolar collapse and induction of ER-stress in AEC2. In vivo pharmacological inhibition of Napsin A results in the development of AEC2 injury and overt lung fibrosis. We also demonstrate that Notch1 signaling is already activated early in IPF and determines AEC2 fate by inhibiting differentiation (reduced lamellar body compartment, reduced capacity to process hydrophobic SP) and by causing increased epithelial proliferation and development of lung fibrosis, putatively via altered JAK/Stat signaling in AEC2. Conversely, inhibition of Notch signaling in IPF-PCLS improved surfactant processing capacity of AEC2s and reversed fibrosis.

CONCLUSION: Notch1 is a central regulator of AEC2 fate in IPF. It induces alveolar epithelial proliferation, loss of Napsin A and of surfactant proprotein processing and it contributes to fibroproliferation.

PMID:36047984 | DOI:10.1164/rccm.202105-1284OC

Front Immunol. 2022 Aug 15;13:901349. doi: 10.3389/fimmu.2022.901349. eCollection 2022.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective curative therapy. Recent evidence shows increased circulating myeloid-derived suppressor cells (MDSCs) in cancer, inflammation, and fibrosis, with some of these cells expressing B7H3. We sought to investigate the role of MDSCs in IPF and its potential mediation via B7H3. Here we prospectively collected peripheral blood samples from IPF patients to analyze for circulating MDSCs and B7H3 expression to assess their clinical significance and potential impact on co-cultured lung fibroblasts and T-cell activation. In parallel, we assess MDSC recruitment and potential B7H3 dependence in a mouse model of pulmonary fibrosis. Expansion of MDSCs in IPF patients correlated with disease severity. Co-culture of soluble B7H3 (sB7H3)-treated mouse monocytic MDSCs (M-MDSCs), but not granulocytic MDSCs (G-MDSCs), activated lung fibroblasts and myofibroblast differentiation. Additionally, sB7H3 significantly enhanced MDSC suppression of T-cell proliferation. Activated M-MDSCs displayed elevated TGFβ and Arg1 expression relative to that in G-MDSCs. Treatment with anti-B7H3 antibodies inhibited bone marrow-derived MDSC recruitment into the bleomycin-injured lung, accompanied by reduced expression of inflammation and fibrosis markers. Selective telomerase reverse transcriptase (TERT) deficiency in myeloid cells also diminished MDSC recruitment associated with the reduced plasma level of sB7H3, lung recruitment of c-Kit+ hematopoietic progenitors, myofibroblast differentiation, and fibrosis. Lung single-cell RNA sequencing (scRNA-seq) revealed fibroblasts as a predominant potential source of sB7H3, and indeed the conditioned medium from activated mouse lung fibroblasts had a chemotactic effect on bone marrow (BM)-MDSC, which was abolished by B7H3 blocking antibody. Thus, in addition to their immunosuppressive activity, TERT and B7H3-dependent MDSC expansion/recruitment from BM could play a paracrine role to activate myofibroblast differentiation during pulmonary fibrosis with potential significance for disease progression mediated by sB7H3.

PMID:36045668 | PMC:PMC9420866 | DOI:10.3389/fimmu.2022.901349

Respir Res. 2022 Sep 1;23(1):226. doi: 10.1186/s12931-022-02155-x.

ABSTRACT

BACKGROUND: Patients with interstitial lung disease (ILD) are at high risk of severe COVID-19 infection. Additionally, their anti-inflammatory and antifibrotic treatment may cause immunosuppression. Nevertheless, their ability to mount an adequate immune response to messenger RNA SARS-CoV-2 vaccines was not evaluated. Therefore, we aimed to evaluate the humoral response after the BNT162b2 vaccine among idiopathic pulmonary fibrosis (IPF) patients treated with antifibrotic therapy and among non-IPF ILD patients treated with anti-inflammatory therapy.

METHODS: We conducted an observational prospective cohort study to evaluate the level of anti-spike (S-IgG) antibodies after two doses of the BNT162b2 vaccine in patients with ILD. The cohort included 40 patients with idiopathic pulmonary fibrosis (IPF) treated with anti-fibrotic therapy and 29 patients with non-IPF ILD treated with anti-inflammatory therapy. For S-IgG titer measurement, one serology test was drawn from all patients 4-6 months after the second vaccine dose. In addition a control group matched for age and sex was created from a healthy control cohort of 107 patients. The study was conducted in Rabin Medical Center (Israel) between June and August 2021.

RESULTS: All patients in the anti-fibrotic arm were seropositive (40/40), corresponding to the matched control group (P = 1.0). The anti-fibrotic arm had a significantly lower median antibody titer in comparison to the matched control group (361.10 [IQR, 207-811] AU/ml vs. 820.75 [IQR, 459-1313] AU/ml; P < 0.001). Only 48.3% (14/29) of patients in the anti-inflammatory arm were seropositive in comparison to 100% (29/29) in the healthy control group (P < 0.001). The anti-inflammatory arm had a significantly lower median antibody titer in comparison to the healthy control group (39.6 [IQR, 4.25-165] AU/ml vs. 970.1 [IQR, 505-1926] AU/ml; P < 0.001).

CONCLUSION: IPF patients treated with antifibrotic therapy mount an adequate immune response after 2 doses of the BNT162b2 vaccine, and maintain a 100% seropositivity rate 4-6 months after vaccination. However, their antibody titer was reduced in comparison to a healthy control group. Among patients with non-IPF ILD treated with anti-inflammatory therapy, 48% were seronegative 4-6 months after the second vaccine dose. Moreover, treatment with rituximab caused significant immunosuppression, even in comparison to other anti-inflammatory treatments.

PMID:36045374 | DOI:10.1186/s12931-022-02155-x

Ann Am Thorac Soc. 2022 Aug 31. doi: 10.1513/AnnalsATS.202202-136OC. Online ahead of print.

ABSTRACT

RATIONALE: Chronic respiratory diseases, the third leading cause of death worldwide, have been associated with significant morbidity, mortality, and increased economic burden, which make a profound impact on individuals and communities. However, limited research has delineated complex relationships between specific sociodemographic disparities and chronic respiratory disease outcomes among US counties.

OBJECTIVE: To assess the association of county-level sociodemographic vulnerabilities with chronic respiratory diseases mortality in the US.

METHODS: Chronic respiratory diseases mortality data among US counties for 2014-2018 was obtained from the Centers for Disease Control and Prevention, Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database. Social Vulnerability Index (SVI), including subindices of Socioeconomic Status, Household Composition & Disability, Minority Status & Language, and Housing Type & Transportation, is a composite, percentile-based measure developed by the CDC to evaluate county-level sociodemographic vulnerabilities to disasters. We examined county-level sociodemographic characteristics from the SVI and classified the percentile rank into quartiles, with higher quartile indicating greater vulnerability. The associations between chronic respiratory diseases mortality and overall SVI, its four subindices, and each county characteristic were analyzed by negative binomial regression.

RESULTS: From 2014 to 2018, the age-adjusted mortality per 1,000,000 population attributed to chronic lower respiratory disease (CLRD) was 406.4 (95% CI: 405.5-407.3); chronic obstructive pulmonary disease (COPD), 393.7 (392.8-394.6); Asthma, 10.0 (9.9-10.2); interstitial lung disease (ILD), 50.5 (50.1-50.8); idiopathic pulmonary fibrosis (IPF), 37.0 (36.7-37.3); and Sarcoidosis, 5.3 (5.2-5.4). Counties in the higher quartile of overall SVI were significantly associated with greater diseases mortality (CLRD, incidence rate ratios: 4th versus 1st quartile, 1.43 [95% CI: 1.39-1.48]; COPD, 1.44 [1.39-1.49]; Asthma, 2.06 [1.71-2.48]; ILD, 1.07 [1.02-1.13]; IPF, 1.14 [1.06-1.22]; Sarcoidosis, 2.01 [1.44-2.81]). Additionally, higher mortality was also found in counties in the higher quartile of each subindex and most sociodemographic characteristics.

CONCLUSIONS: Chronic respiratory diseases mortalities were significantly associated with county-level sociodemographic determinants as measured by the SVI in the US. These findings suggested sociodemographic determinants may add a considerable barrier to establishing health equity. Multilevel public health strategies and clinical interventions addressing inequitable outcomes of chronic respiratory diseases should be developed and targeted on areas with greater social vulnerability and disadvantage.

PMID:36044720 | DOI:10.1513/AnnalsATS.202202-136OC

Inflammopharmacology. 2022 Aug 31. doi: 10.1007/s10787-022-01027-6. Online ahead of print.

ABSTRACT

Pirfenidone (PFN) is an anti-fibrotic drug with significant anti-inflammatory property used for treatment of fibrotic conditions such as idiopathic pulmonary fibrosis (IPF). In the coronavirus disease 2019 (Covid-19) era, severe acute respiratory syndrome 2 (SARS-CoV-2) could initially lead to acute lung injury (ALI) and in severe cases may cause acute respiratory distress syndrome (ARDS) which is usually resolved with normal lung function. However, some cases of ALI and ARDS are progressed to the more severe critical stage of pulmonary fibrosis commonly named post-Covid-19 pulmonary fibrosis which needs an urgent address and proper management. Therefore, the objective of the present study was to highlight the potential role of PFN in the management of post-Covid-19 pulmonary fibrosis. The precise mechanism of post-Covid-19 pulmonary fibrosis is related to the activation of transforming growth factor beta (TGF-β1), which activates the release of extracellular proteins, fibroblast proliferation, fibroblast migration and myofibroblast conversion. PFN inhibits accumulation and recruitment of inflammatory cells, fibroblast proliferation, deposition of extracellular matrix in response to TGFβ1 and other pro-inflammatory cytokines. In addition, PFN suppresses furin (TGFβ1 convertase activator) a protein effector involved in the entry of SARS-CoV-2 and activation of TGFβ1, and thus PFN reduces the pathogenesis of SARS-CoV-2. Besides, PFN modulates signaling pathways such as Wingless/Int (Wnt/β-catenin), Yes-Associated Protein (YAP)/Transcription Co-Activator PDZ Binding Motif (TAZ) and Hippo Signaling Pathways that are involved in the pathogenesis of post-Covid-19 pulmonary fibrosis. In conclusion, the anti-inflammatory and anti-fibrotic properties of PFN may attenuate post-Covid-19 pulmonary fibrosis.

PMID:36044102 | DOI:10.1007/s10787-022-01027-6

Inflammation. 2022 Aug 31. doi: 10.1007/s10753-022-01733-x. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD) is a frequent extra-articular manifestation of rheumatoid arthritis (RA) and increases mortality in patients with RA. Early identification of ILD, especially the usual interstitial pneumonia (UIP) pattern with a poor prognosis, is important for guiding treatment of RA-ILD and preventing damage resulting from a delay in diagnosis. Interleukin-36 (IL-36) cytokines are involved in connective tissue diseases. However, IL-36 expression in RA-ILD is unknown. In this study, the clinical relevance of plasma IL-36 cytokines was evaluated in 39 patients with RA-ILD and three other groups (30 healthy controls [HCs], 35 RA patients without ILD, and 27 patients with idiopathic pulmonary fibrosis [IPF]) in the Chinese population. Plasma IL-36α and IL-36γ concentrations were elevated in patients with RA-ILD compared with those in HCs and patients with RA. RA-ILD patients with UIP pattern had higher plasma IL-36γ concentrations than those with RA-ILD without UIP, but these were lower than those in patients with IPF. Receiver operating curve analysis suggested that IL-36α and IL-36γ were potential biomarkers for identifying ILD in patients with RA. Additionally, the optimal cutoff value of IL-36γ for distinguishing RA-ILD with the UIP pattern from RA-ILD without UIP was 555.40 pg/mL and that for distinguishing RA-ILD from IPF was 655.10 pg/mL. No significant difference in plasma IL-36β or IL-36Ra concentrations was found between patients with RA-ILD and the three other groups. We also found that the lungs originating from different types of patients with PF, including RA-ILD and IPF, and those from mice following bleomycin-induced PF were characterized by increased IL-36γ expression. Our findings suggest that using IL-36 cytokines to identify patients with RA for further ILD workups may provide additional diagnostic value to the current clinically available assays. Moreover, IL-36γ may help to identify the presence of the UIP pattern in patients with RA-ILD and to discriminate RA-ILD from IPF.

PMID:36044099 | DOI:10.1007/s10753-022-01733-x

Clin Sci (Lond). 2022 Aug 31;136(16):1229-1240. doi: 10.1042/CS20210878.

ABSTRACT

Fibrosis involving the lung may occur in many settings, including in association with known environmental agents, connective tissue diseases, and exposure to drugs or radiation therapy. The most common form is referred to as 'idiopathic' since a causal agent or specific association has not been determined; the strongest risk factor for idiopathic pulmonary fibrosis is aging. Emerging studies indicate that targeting certain components of aging biology may be effective in mitigating age-associated fibrosis. While transforming growth factor-β1 (TGF-β1) is a central mediator of fibrosis in almost all contexts, and across multiple organs, it is not feasible to target this canonical pathway at the ligand-receptor level due to the pleiotropic nature of its actions; importantly, its homeostatic roles as a tumor-suppressor and immune-modulator make this an imprudent strategy. However, defining targets downstream of its receptor(s) that mediate fibrogenesis, while relatively dispenable for tumor- and immune-suppressive functions may aid in developing safer and more effective therapies. In this review, we explore molecular targets that, although TGF-β1 induced/activated, may be relatively more selective in mediating tissue fibrosis. Additionally, we explore epigenetic mechanisms with global effects on the fibrogenic process, as well as metabolic pathways that regulate aging and fibrosis.

PMID:36043396 | DOI:10.1042/CS20210878

Pan Afr Med J. 2022 Jun 3;42:92. doi: 10.11604/pamj.2022.42.92.35264. eCollection 2022.

NO ABSTRACT

PMID:36034006 | PMC:PMC9379445 | DOI:10.11604/pamj.2022.42.92.35264

BMC Pulm Med. 2022 Aug 30;22(1):329. doi: 10.1186/s12890-022-02122-8.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) often has significant diagnostic delay. At present it is not well-known what factors associate with time to diagnosis and if this is associated with survival after the diagnosis. There has also been increasing attention for interstitial lung abnormalities on chest CT-scans. In this study we assessed what factors associate with time to diagnosis in patients with IPF, and whether early stages of pulmonary fibrosis can be seen on chest X-rays prior to the start of symptoms.

METHODS: In this retrospective study, 409 Dutch patients with IPF were included. Clinical characteristics, including patient demographics, medical history, time of start of symptoms, time of first visit to pulmonologist, and any previous radiographic imaging reports were collected from patient records.

RESULTS: In 96 patients (23%) a chest X-ray was available that had been made prior to the start of symptoms (median of 50.5 months (IQR 26.3-83.3 months)), and this showed potential interstitial lung abnormalities in 56 patients (58%). The median time from the start of symptoms to the final diagnosis was 24.0 months (interquartile range 9.0-48.0 months). In a multivariate model that corrected for diffusion capacity of the lung for carbon monoxide, forced vital capacity, sex, and age at diagnosis, time to diagnosis did not associate with survival (hazard ratio 1.051 (95% CI 0.800-1.380; p = 0.72)).

CONCLUSIONS: There is a significant diagnostic delay for patients with IPF, but longer time to diagnosis did not associate with survival. Interstitial lung abnormalities were seen in more than half of the patients in whom a chest X-ray had been made prior to the start of symptoms. This illustrates that a computed tomography scan should be strongly considered for analysis of unexplained abnormalities on a chest X-ray. This could facilitate early detection and possibly prevention of disease progression for patients with pulmonary fibrosis.

PMID:36038862 | DOI:10.1186/s12890-022-02122-8

Zhonghua Er Ke Za Zhi. 2022 Sep 2;60(9):930-934. doi: 10.3760/cma.j.cn112140-20220422-00364.

ABSTRACT

Objective: To analyze the clinical characteristics and prognosis of 6 children with idiopathic interstitial pneumonia (IIP). Methods: This retrospective study analyzed the clinical manifestations, examinations, treatment and prognosis of 6 children with IIP who were hospitalized in Children's Hospital of Nanjing Medical University from January 2015 to March 2020. Results: Of the 6 children, 2 were males and 4 were females, aged 4.8 to10.6 years. All children had a subacute onset, and presented with cough, shortness of breath and cyanosis. The lung high-resolution CT (HRCT) showed diffuse patchiness in bilateral lung fields in all the children and reticular pattern in 2 cases. Pulmonary function test found moderate to severe mixed defect in 5 children. Lung biopsy was performed in 4 children. All of the 6 children were treated with systemic glucocorticoids, of whom 2 cases had additional inhaled glucocorticoids. Four children were finally diagnosed as cryptogenic organizing pneumonia (COP), whose lung HRCT return to normal in 1-11 months. Two children were finally diagnosed as nonspecific interstitial pneumonia (NSIP), and had long-term residual fibrosis on lung HRCT. The 6 children were followed up for 1 year to 6 years and 5 months after discontinuation of systemic glucocorticoids, and all had no recurrence. Conclusions: The clinical characteristics of IIP in children are subacute onset presented with cough, shortness of breath, cyanosis and diffuse patchiness in bilateral lungs on HRCT. The common subtypes of IIP in children are COP and NSIP. Systemic glucocorticoid is effective for IIP in children and there is a good prognosis overall.

PMID:36038304 | DOI:10.3760/cma.j.cn112140-20220422-00364

Am J Respir Cell Mol Biol. 2022 Aug 29. doi: 10.1165/rcmb.2022-0174OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a poorly understood, progressive lethal lung disease with no known cure. In addition to alveolar epithelial cell (AEC) injury and excessive deposition of extracellular matrix proteins, chronic inflammation is a hallmark of IPF. Literature suggests that the persistent inflammation seen in IPF primarily consists of monocytes and macrophages. Recent work demonstrates that monocyte-derived alveolar macrophages (moAMs) drive lung fibrosis, but further characterization of critical moAM cell attributes is necessary. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an important EGFR (epidermal growth factor receptor) ligand that has essential roles in angiogenesis, wound healing, keratinocyte migration, and epithelial-mesenchymal transition. Our past work has shown HB-EGF is a primary marker of profibrotic M2 macrophages, and this study seeks to characterize myeloid-derived HB-EGF and its primary mechanism of action in bleomycin-induced lung fibrosis using Hbegff/f;Lyz2Cre+ mice. Here, we show that IPF patients and fibrotic mice have increased expression of HB-EGF and that lung macrophages and transitional alveolar epithelial cells of fibrotic mice and humans all express HB-EGF. We also show that Hbegff/f;Lyz2Cre+ mice are protected from bleomycin-induced fibrosis and that this protection is likely multifactorial, caused by decreased CCL2-dependent monocyte migration, decreased fibroblast migration, and decreased contribution of HB-EGF from AEC sources when HB-EGF is removed under the Lyz2Cre promoter.

PMID:36036796 | DOI:10.1165/rcmb.2022-0174OC

Front Cardiovasc Med. 2022 Aug 10;9:987652. doi: 10.3389/fcvm.2022.987652. eCollection 2022.

ABSTRACT

BACKGROUND: To evaluate the effect of oral anticoagulants (OACs) therapy, including vitamin K antagonist (VKA) and direct oral anticoagulants (DOAC) in patients with pulmonary diseases.

METHODS: Literature from PubMed, MEDLINE, and Cochrane Library were screened until June 2022. Studies assessing OACs for pulmonary hypertension (PH), pulmonary embolism (PE), pulmonary fibrosis (PF), or chronic obstructive pulmonary disease (COPD) were evaluated for inclusion.

RESULTS: Our study indicated that in patients with PH, PE, and COPD, OACs could significantly reduce the mortality risk, and the effects of VKA and DOACs without statistical difference in reducing the risk of recurrent embolism events. In patients with sclerosis-associated pulmonary arterial hypertension (SSc-PAH) or idiopathic pulmonary fibrosis (IPF), vitamin K antagonist (warfarin) significantly increased the mortality risk, while DOACs were not. As for the safety outcome of OACs, existing studies indicate that compared with patients treated with warfarin, the users of DOAC have a lower risk of major bleeding, while there is no statistical significance between them in non-major bleeding events. In current guidelines, the anticoagulation regimen for patients with pulmonary disease has not been defined. The results of our study confirm that DOACs (apixaban, rivaroxaban, dabigatran, and edoxaban) are superior to VKAs in the efficacy and safety outcomes of patients with pulmonary disease.

CONCLUSIONS: Oral anticoagulant therapy brings benefits to patients with PH, PE, or COPD, while the anticoagulation regimen for patients with SSc-PAH or IPF requires serious consideration. Compared with VKA, DOAC is a non-inferior option for anticoagulation in pulmonary disease treatment. Further studies are still needed to provide more reliable evidence about the safety outcome of pulmonary disease anticoagulation.

PMID:36035947 | PMC:PMC9399807 | DOI:10.3389/fcvm.2022.987652