Medium-term exposure to size-fractioned particulate matter and asthma exacerbations in China: A longitudinal study of asthmatics with poor medication adherence.

BACKGROUND: Studies have shown that short- and long-term exposure to particulate matter (PM) can increase the risk of asthma morbidity and mortality. However, the effect of medium-term exposure remains unknown. We aim to examine the effect of medium-term exposure to size-fractioned PM on asthma exacerbations among asthmatics with poor medication adherence. METHODS: We conducted a longitudinal study in China based on the National Mobile Asthma Management System Project that specifically and routinely followed asthma exacerbations in asthmatics with poor medication adherence from April 2017 to May 2019. High-resolution satellite remote-sensing data were used to estimate each participant's medium-term exposure (on average 90 days) to size-fractioned PM (PM1, PM2.5, and PM10) based on the residential address and the date of the follow-up when asthma exacerbations (e.g., hospitalizations and emergency room visits) occurred or the end of the follow-up. The Cox proportional hazards model was employed to examine the hazard ratio of asthma exacerbations associated with each PM after controlling for sex, age, BMI, education level, geographic region, and temperature. RESULTS: Modelling results revealed nonlinear exposure-response associations of asthma exacerbations with medium-term exposure to PM1, PM2.5, and PM10. Specifically, for emergency room visits, we found an increased hazard ratio for PM1 above 22.8 µg/m3 (1.060, 95 % CI: 1.025-1.096, per 1 µg/m3 increase), PM2.5 above 38.2 µg/m3 (1.032, 95 % CI: 1.010-1.054), and PM10 above 78.6 µg/m3 (1.019, 95 % CI: 1.006-1.032). For hospitalizations, we also found an increased hazard ratio for PM1 above 20.3 µg/m3 (1.055, 95 % CI: 1.001-1.111) and PM2.5 above 39.2 µg/m3 (1.038, 95 % CI: 1.003-1.074). Furthermore, the effects of PM were greater for a longer exposure window (90-180 days) and among participants with a high BMI. CONCLUSION: This study suggests that medium-term exposure to PM is associated with an increased risk of asthma exacerbations in asthmatics with poor medication adherence, with a higher risk from smaller PM.

IL-17A promotes lung fibrosis through impairing mitochondrial homeostasis in type II alveolar epithelial cells.

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.

Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases.

Follistatin-like 1 (FSTL1) is a matricellular protein that is upregulated during development and disease, including idiopathic pulmonary fibrosis (IPF), keloid, and arthritis. The profibrotic and pro-inflammatory roles of FSTL1 have been intensively studied during the last several years, as well as in this report. We screened and identified epitope-specific monoclonal neutralizing antibodies (nAbs) to functionally block FSTL1. FSTL1 nAbs attenuated bleomycin-induced pulmonary and dermal fibrosis in vivo and transforming growth factor (TGF)-ß1-induced dermal fibrosis ex vivo in human skin. In addition, FSTL1 nAbs significantly reduced existing lung fibrosis and skin fibrosis in experimental models. FSTL1 nAbs exerted their potent antifibrotic effects via reduced TGF-ß1 responsiveness and subsequent myofibroblast activation and extracellular matrix production. We also observed that FSTL1 nAbs attenuated the severity of collagen-induced arthritis in mice, which was accompanied by reduced inflammatory responses in vitro. Our findings suggest that FSTL1 nAbs are a promising new therapeutic strategy for the treatment of multiple organ fibrosis and systemic autoimmune diseases.

Small airway dysfunction in Chinese patients with idiopathic pulmonary fibrosis.

BACKGROUND: Recent years, idiopathic pulmonary fibrosis (IPF) is thought to be a disease of alveoli as well as small airways. This study aimed to demonstrate the clinical feature, predictor, and prognosis of small airway dysfunction (SAD) in Chinese patients with IPF. METHODS: We enrolled 416 patients with IPF who hospitalized in Beijing Chao-Yang Hospital from 2000 to 2014 in this study, and the follow-up ended at December 2016. We collected demographic information, clinical examination results, spirometry results, HRCT results, and blood gas results during the study. Logistic regression analysis was used to identify the predictor for SAD. The COX proportional hazard model was used to analysis the prognosis effect of SAD. RESULTS: Among all the participants, 165 (39.66%) patients had SAD. FEV1 (% predicted) and FEV3/FVC were significantly associated with SAD in patients with IPF. IPF patients with lower FEV1 (% predicted, OR 30.04, 95% CI 9.61-93.90) and FEV3/FVC (OR 77.76, 95% CI 15.44-391.63) had increased risk for SAD. Patients with SAD were associated with significantly increased risk of mortality in patients with IPF (HR 1.73, 95% CI 1.02-2.92), as well as in IPF patients without other pulmonary comorbidities (COPD, emphysema, and asthma). CONCLUSIONS: Spirometry-defined SAD was like 40% in patients with IPF. Lower FEV1 (% predicted) and FEV3/FVC were main predictors for SAD. IPF patients with SAD showed poorer prognosis.

Lung Myofibroblasts Promote Macrophage Profibrotic Activity through Lactate-induced Histone Lactylation.

Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-ß1 (transforming growth factor-ß1)-induced lung myofibroblasts and in the BAL fluids (BALFs) from mice with TGF-ß1- or bleomycin-induced lung fibrosis. Importantly, the media and BALFs promoted profibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the profibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and profibrotic gene expression were mediated by p300, as evidenced by their diminished concentrations in p300-knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.

ATF4 Mediates Mitochondrial Unfolded Protein Response in Alveolar Epithelial Cells.

Although endoplasmic reticulum (ER) unfolded protein response (UPRER) is well known, mitochondrial unfolded protein response (UPRmt) has not been recognized in alveolar epithelial cells. Furthermore, ER stress and mitochondrial dysfunction are frequently encountered in alveolar epithelial cells from an array of lung disorders. However, these two scenarios have been often regarded as separate mechanisms contributing to the pathogeneses. It is unclear whether there is interplay between these two phenomena or an integrator that couples these two signaling cascades in the stressed alveolar epithelial cells from those pathologies. In this study, we defined UPRmt in alveolar epithelial cells and identified ATF4 (activating transcription factor 4), but not ATF5, as the key regulator of UPRmt. We found that UPRER led to UPRmt and mitochondrial dysfunction in an ATF4-dependent manner. In contrast, mitochondrial stresses did not activate UPRER. We found that alveolar epithelial ATF4 and UPRmt were induced in aged mice with experimental pulmonary fibrosis as well as in patients with idiopathic pulmonary fibrosis. Finally, we found that the inducible expression of ATF4 in mouse alveolar epithelial cells aggravated pulmonary UPRmt, lung inflammation, body weight loss, and death upon bleomycin-induced lung injury. In conclusion, ER stress induces ATF4-dependent UPRmt and mitochondrial dysfunction, indicating a novel mechanism by which ER stress contributes to the pathogeneses of a variety of pulmonary disorders.

Inhibition of Glutaminase 1 Attenuates Experimental Pulmonary Fibrosis.

It has been increasingly recognized lately that aberrant cellular metabolism plays an important role in the pathogenesis of pulmonary fibrosis. In our previous systemic studies, we found that human lung myofibroblasts undergo glutaminolytic reprogramming, which is mediated by an increased expression of glutaminase (Gls) 1. We showed that augmented glutaminolysis critically regulates collagen production by promoting its stabilization in human lung myofibroblasts. Our study indicates that lung fibroblast Gls1 is a promising therapeutic target for this disease. In this investigation, we primarily focused on delineating the in vivo role of fibroblast Gls1 in mouse models of pulmonary fibrosis and determining the efficacy of Gls1 inhibition in treating this pathology. We now show that fibroblast Gls1 is upregulated in fibrotic mouse lungs. We present evidence that mice with ablation of fibroblast Gls1 are protected from bleomycin-induced lung fibrosis. We show that the Gls1 inhibitor, CB-839, is therapeutically efficacious in treating both bleomycin- and transforming growth factor-ß1-induced pulmonary fibrosis. Our study has thus established a solid rationale for advancing Gls1 inhibitors, particularly CB-839, to the next stage of testing in the treatment of this disease.

Hydrogen inhalation attenuated bleomycin-induced pulmonary fibrosis by inhibiting transforming growth factor-ß1 and relevant oxidative stress and epithelial-to-mesenchymal transition.

NEW FINDINGS: • What is the central question of this study? The aim was to explore the effects and underlying mechanisms of H2 on bleomycin-induced pulmonary fibrosis. • What are the main findings and its importance? Our results indicate that, in bleomycin-induced pulmonary fibrosis, H2 inhalation attenuated oxidative stress and reversed the pulmonary epithelial-to-mesenchymal transition process by reducing reactive oxygen species production and inhibiting the expression of transforming growth factor-ß1, α-smooth muscle actin and collagen I to improve fibrotic injury and exert anti-fibrogenic effects. Thus, H2 inhalation has promising therapeutic potential as a useful adjuvant treatment for patients with idiopathic pulmonary fibrosis, which deserves further study and evaluation. ABSTRACT: Hydrogen (H2 ) can protect against tissue damage. The effect of H2 inhalation therapy on the pathogenesis of pulmonary fibrosis remains unknown. This study was designed to explore the effects and underlying mechanisms of H2 inhalation on bleomycin (BLM)-induced pulmonary fibrosis. A rat model of pulmonary fibrosis was established with BLM. Rats were randomly divided into control and H2 inhalation groups. Haematoxylin and Eosin staining and Mason's Trichrome staining were performed to evaluate pulmonary fibrosis injury, inflammatory cell infiltration, structural disorder and collagen deposition. qRT-PCR and western blot assays were used to determine the expression of TNF-α, TGF-ß1, α-SMA, E-cadherin, N-cadherin, vimentin, VEGF and collagen type I at both mRNA and protein levels. The contents of reactive oxygen species, TGF-ß1, TNF-α, malondialdehyde and hydroxyproline were determined with biochemical test kits or ELISA kits. Bleomycin-stimulated rats exhibited typical symptoms of pulmonary fibrosis, which featured an increase in collagen deposition, alveolitis, fibrosis and parenchymal structural disorder in the lung. However, BLM-induced oxidative stress was attenuated by H2 inhalation therapy, which reduced the contents of reactive oxygen species, malondialdehyde and hydroxyproline, enhanced the activity of glutathione peroxidase and decreased the expression of TGF-ß1 and TNF-α. In addition, H2 inhalation also inhibited BLM-induced epithelial-to-mesenchymal transition by inhibiting TGF-ß1, increasing the expression level of the epithelial cell marker E-cadherin, and decreasing the expression level of the mesenchymal cell marker vimentin in a time-dependent manner. In addition, H2 inhalation downregulated α-SMA expression and suppressed collagen I generation, exerting anti-fibrogenic effects. Hydrogen inhalation therapy attenuates BLM-induced pulmonary fibrosis by inhibiting TGF-ß1, relevant oxidative stress and epithelial-to-mesenchymal transition.

Down-regulation of USP13 mediates phenotype transformation of fibroblasts in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by fibroblastic foci and progressive scarring of the pulmonary parenchyma. IPF fibroblasts display increased proliferation and enhanced migration and invasion, analogous to cancer cells. This transformation-like phenotype of fibroblasts plays an important role in the development of pulmonary fibrosis, but the mechanism for this is not well understood. METHODS: In this study, we compared gene expression profiles in fibrotic lung tissues from IPF patients and normal lung tissues from patients with primary spontaneous pneumothorax using a cDNA microarray to examine the mechanisms involved in the pathogenesis of IPF. In a cDNA microarray, we found that USP13 was decreased in lung tissues from patients with IPF, which was further confirmed by results from immunohistochemistry and western blot assays. Then, we used RNA interference in MRC-5 cells to inhibit USP13 and evaluated its effects by western blot, real-time RT-PCR, bromodeoxyuridine incorporation, and transwell assays. We also used co-immunoprecipitation and immunofluorescence staining to identify the correlation between USP13 and PTEN in IPF. RESULTS: USP13 expression levels were markedly reduced in fibroblastic foci and primary IPF fibroblast lines. The depletion of USP13 resulted in the transformation of fibroblasts into an aggressive phenotype with enhanced proliferative, migratory, and invasive capacities. Additionally, USP13 interacted with PTEN and mediated PTEN ubiquitination and degradation in lung fibroblasts. CONCLUSIONS: Down-regulation of USP13 mediates PTEN protein loss and fibroblast phenotypic change, and thereby plays a crucial role in IPF pathogenesis.

[Role and underlying mechanism of IGF-I/ERK signaling pathway in lung fibrosis].

OBJECTIVE: To explore the role and underlying mechanisms of insulin-like growth factor I (IGF-I)/extracellular signal-regulated kinase (ERK) signaling pathway in lung fibrosis. METHODS: Alveolar epithelial cell A549 was used. The expressions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in A549 culture media stimulated by IGF-I were determined by enzyme-linked immunosorbent assay (ELISA). ERK inhibitor U0126 was used. And there were three groups of control, IGF-I stimulation and RK inhibitor plus IGF-I stimulation. The activity of ERK in three groups was measured by Western blot. The mRNA level and protein concentration of MMP-2 and MMP-9 in three groups were examined by quantitative real-time-polymerase chain reaction (qRT-PCR) and ELISA. RESULTS: The protein concentrations of MMP-2 and MMP-9 in cell culture media increased in 50, 100 ng/ml IGF-I groups as compared with 0 ng/ml IGF-I group ((18.30 ± 0.11), (21.80 ± 0.09) vs (13.52 ± 0.19) ng/ml and (0.34 ± 0.01), (0.39 ± 0.01) vs (0.25 ± 0.01) ng/ml, P < 0.001). And the protein concentrations of MMP-2 and MMP-9 in 100 ng/ml IGF-I group increased versus 50 ng/ml IGF-I group (P < 0.01). IGF-I stimulation group increased the expression of p-ERK1/2 versus control group (0.40 ± 0.01 vs 0.23 ± 0.02, P < 0.05) while ERK inhibitor plus IGF-I stimulation group decreased the expression of p-ERK1/2 versus IGF-I stimulation group (0.14 ± 0.03 vs 0.40 ± 0.01, P < 0.01). ERK inhibitor plus IGF-I stimulation group inhibited the mRNA levels of MMP-2 and MMP-9 versus IGF-I stimulation group (0.88 ± 0.03 vs 1.17 ± 0.05 and 0.82 ± 0.23 vs 1.81 ± 0.27, both P < 0.05) and decreased the concentrations of MMP-2 and MMP-9 in culture media versus IGF-I stimulation group ((21.70 ± 0.32) vs (29.15 ± 0.34) ng/ml and (0.22 ± 0.01) vs (0.29 ± 0.01) ng/ml, both P < 0.01). CONCLUSIONS: IGF-I induces the expressions of MMP-2 and MMP-9 in alveolar epithelial cell through ERK signaling pathway. And it is associated with the disruption of epithelial basement membrane and the development of lung fibrosis.

Interleukin-17A plays a key role in pulmonary fibrosis following Propionibacterium acnes-induced sarcoidosis-like inflammation.

Sarcoidosis is a granulomatous disease of unknown etiology, with limited therapeutic options. Chronic sarcoidosis can result in pulmonary fibrosis and can be lethal. Enhanced expression of pro-inflammatory cytokines, such as interleukin-17A (IL-17A), has been observed in sarcoid granulomas in humans. However, the role of IL-17A in the pathogenesis of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis and its potential therapeutic effects remain unclear. This study investigated whether IL-17A is critical in granulomatosis and its role in chronic inflammation in a profibrotic manner. Wild-type and IL-17A-knockout C57BL/6 mice were repeatedly challenged with heat-killed Propionibacterium acnes (PA) to induce sarcoidosis-like granulomata and sarcoidosis-related pulmonary fibrosis. Wild-type mice with granulomatosis were treated with anti-IL-17A antibody. Administration of PA enhanced the expression of IL-17A, granulomatosis, and fibrosis in mouse lungs after boost stimulation. Neither granulomata nor fibrosis were observed in IL-17A-knockout mice, even in the presence of interferon-γ enhancement. Neutralizing IL-17A antibody reduced inflammatory cells in bronchoalveolar lavage fluid and ameliorated both granulomatosis and fibrosis in sarcoidosis mice. In conclusion, our data demonstrate that IL-17A plays a critical role in PA-induced sarcoidosis-like inflammation in both granulomatosis inflammation and disease progression to pulmonary fibrosis, thus providing novel insights into the treatment of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis.

Imbalanced distribution of regulatory T cells and Th17.1 cells in the peripheral blood and BALF of sarcoidosis patients: relationship to disease activity and the fibrotic radiographic phenotype.

Rationale: Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. Objectives: We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. Methods: We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. Measurements and results: An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. Conclusion: A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.

Zinc defends against Parthanatos and promotes functional recovery after spinal cord injury through SIRT3-mediated anti-oxidative stress and mitophagy.

INTRODUCTION: Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as motor, sensory, and autonomic dysfunction below the level of damage. Our previous studies confirmed the ability of zinc to protect mitochondria, protect neurons and promote spinal cord recovery. However, the role of zinc in Parthanatos is unknown. AIM: We investigated the effects of zinc in Parthanatos from oxidative stress and mitophagy. We elucidated the role of SIRT3 in providing new ideas for treating spinal cord injury. THE RESULTS: Zinc protected SCI mice by regulating Parthanatos. On the one hand, zinc eliminated ROS directly through SIRT3 deacetylation targeting SOD2 to alleviate Parthanatos. On the other hand, zinc eliminated ROS indirectly through SIRT3-mediated promotion of mitophagy to alleviate Parthanatos. CONCLUSION: Zinc defends against Parthanatos and promotes functional recovery after spinal cord injury through SIRT3-mediated anti-oxidative stress and mitophagy.

Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes.

BACKGROUND: The presence of fibrosis is a criterion for subtype classification in the newly updated hypersensitivity pneumonitis (HP) guidelines. The present study aimed to summarize differences in clinical characteristics and prognosis of non-fibrotic hypersensitivity pneumonitis (NFHP) and fibrotic hypersensitivity pneumonitis (FHP) and explore factors associated with the presence of fibrosis. METHODS: In this prospective cohort study, patients diagnosed with HP through a multidisciplinary discussion were enrolled. Collected data included demographic and clinical characteristics, laboratory findings, and radiologic and histopathological features. Logistic regression analyses were performed to explore factors related to the presence of fibrosis. RESULTS: A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP patients and 115 (56.9%) FHP patients. Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP. Serum levels of carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 153, gastrin-releasing peptide precursor, squamous cell carcinoma antigen, and antigen cytokeratin 21-1, and count of bronchoalveolar lavage (BAL) eosinophils were higher in the FHP group than in the NFHP group. BAL lymphocytosis was present in both groups, but less pronounced in the FHP group. Multivariable regression analyses revealed that older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors for the development of FHP. Twelve patients developed adverse outcomes, with a median survival time of 12.5 months, all of whom had FHP. CONCLUSIONS: Older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors associated with the development of FHP. Prognosis of patients with NFHP was better than that of patients with FHP. These results may provide insights into the mechanisms of fibrosis in HP.

External validation of the GAP model in Chinese patients with idiopathic pulmonary fibrosis.

INTRODUCTION: The GAP model was widely used as a simple risk "screening" method for patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We sought to validate the GAP model in Chinese patients with IPF to evaluate whether it can accurately predict the risk for mortality. METHODS: A total of 212 patients with IPF diagnosed at China-Japan Friendship Hospital from 2015 to 2019 were enrolled. The latest follow-up ended in September 2022. Cumulative mortality of each GAP stage was calculated and compared based on Fine-Gray models for survival, and lung transplantation was treated as a competing risk. The performance of the model was evaluated in terms of both discrimination and calibration. RESULTS: The cumulative mortality in patients with GAP stage III was significantly higher than that in those with GAP stage I or II (Gray's test p < 0.0001). The Harrell c-index for the GAP calculator was 0.736 (95% CI: 0.667-0.864). The discrimination for the GAP staging system were similar with that for the GAP calculator. The GAP model overestimated the mortality rate at 1- and 2-year in patients classified as GAP stage I (6.90% vs. 1.77% for 1-year, 14.20% vs. 6.78% for 2-year). CONCLUSIONS: Our findings indicated that the GAP model overestimated the mortality rate in mild group.

A transcriptomics-based meta-analysis identifies a cross-tissue signature for sarcoidosis.

Sarcoidosis is a granulomatous disease of unknown etiology, immunologically characterized by a Th1 immune response. Transcriptome-wide expression studies in various types of sarcoid tissues contributed to better understanding of disease mechanisms. We performed a systematic database search on Gene Expression Omnibus (GEO) and utilized transcriptomic data from blood and sarcoidosis-affected tissues in a meta-analysis to identify a cross-tissue, cross-platform signature. Datasets were further separated into training and testing sets for development of a diagnostic classifier for sarcoidosis. A total of 690 differentially expressed genes were identified in the analysis among various tissues. 29 of the genes were robustly associated with sarcoidosis in the meta-analysis both in blood and in lung-associated tissues. Top genes included LINC01278 (P = 3.11 × 10-13), GBP5 (P = 5.56 × 10-07), and PSMB9 (P = 1.11 × 10-06). Pathway enrichment analysis revealed activated IFN-γ, IL-1, and IL-18, autophagy, and viral infection response. IL-17 was observed to be enriched in peripheral blood specific signature genes. A 16-gene classifier achieved excellent performance in the independent validation data (AUC 0.711-0.964). This study provides a cross-tissue meta-analysis for expression profiles of sarcoidosis and identifies a diagnostic classifier that potentially can complement more invasive procedures.

Case report: Corticosteroid-resistant acute fibrinous and organizing pneumonia with myelodysplastic syndrome.

Acute fibrinous and organizing pneumonia (AFOP) is a lung disease with an unusual pathological pattern. The definitive diagnosis of AFOP relies on pathological evidence of intra-alveolar fibrin exudate, lymphoplasmacytic infiltrate, and the absence of a hyaline membrane. Furthermore, its etiology is difficult to confirm, and corticosteroids are usually effective. Herein, we report the case of a young male who presented with high fever, hemocytopenia, and consolidation in both lungs. The initial misdiagnosis was community-acquired pneumonia. Subsequently, a lung biopsy revealed abundant fibrin and fibroblast exudates in the alveolar spaces, indicating AFOP. In addition, bone marrow biopsy and karyotype analysis demonstrated that the patient simultaneously had myelodysplastic syndrome (MDS) and hemophagocytic lymphohistiocytosis. In this case, the AFOP was considered secondary to MDS; however, the disease did not respond to glucocorticoid treatment or chemotherapy. Hence, AFOP should be considered in patients with underlying hematological diseases, and early identification and diagnosis are important. Furthermore, the management of patients with severe AFOP requires further investigation.

Krebs von den Lungen-6 levels in untreated idiopathic pulmonary fibrosis.

BACKGROUND: Serum Krebs von den Lungen-6 (KL-6) has been reported to be elevated in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The aim of this study was to evaluate the diagnostic value of KL-6 and whether the expression value of KL-6 could indicate the severity of the disease in IPF patients. To address this question, it is necessary to see whether the patients' physical characteristics and other clinical conditions could affect the baseline KL-6 level. DESIGN: We conducted a study of 100 patients who were diagnosed with IPF. Lung function, computed tomography (CT), and serological lab tests data were analyzed. RESULTS: The tests showed that there is a significant elevation of KL-6 in IPF patients compared with other interstitial lung disease (ILD) and healthy controls. It was noted that serum KL-6 is a stable biomarker not affected by lung infection and smoking, though IPF patients with antinuclear antibody (ANA) showed higher KL-6 levels. KL-6, in conjunction with poor pulmonary function and higher radiological fibrosis scores, indicates the severity of the disease but not poor survival. CONCLUSIONS: It is identified that serum KL-6 is a useful noninvasive biomarker to help improve the certainty of IPF diagnosis from other interstitial lung disease and assist evaluation of disease severity and prognosis.

Blood monocyte counts as a prognostic biomarker and predictor in Chinese patients with idiopathic pulmonary fibrosis.

Objectives: We sought to evaluate the prognostic value of blood routine parameters and biochemical parameters, especially inflammation-related biomarkers, and establish an inflammation-related prognostic model in Chinese patients with idiopathic pulmonary fibrosis (IPF). Material/methods: Patients diagnosed as IPF at Beijing Chaoyang Hospital and aged 40 years and older were consecutively enrolled from June 2000 to March 2015, and finally, a total of 377 patients were enrolled in the derivation cohort. The follow-up ended in December 2016. We used Cox proportional hazard model to calculate the hazard ratio (HR) and establish the prognostic model. The discrimination and calibration of the prognostic model were evaluated in an independent validation cohort enrolled from China-Japan Friendship Hospital between January 2015 and December 2019. Results: Multivariate analysis revealed that patients with elevated monocyte-to-red blood cell count ratio (MRR) and monocyte counts showed increased risk of mortality. The clinical-physiological-biomarker (CPB) index and CPB stage we established in this study were a significant predictor, and the C-index for CPB index and CPB stage in the validation cohort was 0.635 (95% CI: 0.558-0.712) and 0.619 (95% CI: 0.544-0.694), respectively. Patients in CPB stage III had the poorest survival. Conclusion: We developed and validated a new inflammation-related prognostic model (CPB index and CPB stage) which was integration of age, gender, FVC (%, predicted), DLCO (%, predicted), Charlson Comorbidity Index, and blood monocyte counts. This prediction model exhibited strong ability in predicting mortality in Chinese patients with IPF.