Ther Clin Risk Manag. 2022 Apr 19;18:429-437. doi: 10.2147/TCRM.S349185. eCollection 2022.

ABSTRACT

BACKGROUND: Correlations between idiopathic pulmonary fibrosis (IPF) and lung cancer have been discussed in many previous studies. In the present work, we evaluated the potential diagnostic value of serum levels of Th17 cell-related cytokines for the detection of lung cancer-associated IPF.

METHODS: Fifty-six patients who had been diagnosed with lung cancer-associated IPF were enrolled, and 59 patients with lung cancer but without IPF were also enrolled, and 60 healthy volunteers were served as the control group. The expression of IL-22, IL-23, and IL-17 was evaluated by enzyme-linked immunosorbent assay (ELISA) kits.

RESULTS: We observed that IL-22, IL-23 as well as IL-17 were significantly increased in the serum of lung cancer patients associated IPF; moreover, the results of ROC curve showed that the expression of IL-22, IL-23 and IL-17 can distinguish the lung cancer patients with lung cancer-associated IPF group; finally, the expression of IL-22, IL-23 and IL-17 was positively correlated with the degree of differentiation and metathesis of the tumor.

CONCLUSION: In conclusion, we first reported that IL-22, IL-23 and IL-17 were elevated in the serum of patients with lung cancer-associated IPF, and our data may provide novel evidence for the prevention and treatment of lung cancer-associated IPF.

PMID:35469293 | PMC:PMC9034872 | DOI:10.2147/TCRM.S349185

Am J Respir Cell Mol Biol. 2022 Apr 25. doi: 10.1165/rcmb.2021-0418OC. Online ahead of print.

ABSTRACT

Immune cells have been implicated in Idiopathic Pulmonary Fibrosis (IPF), but the phenotypes and effector mechanisms of these cells remain incompletely characterized. We performed mass cytometry to quantify immune/inflammatory cell subsets in lungs of 12 patients with IPF and 15 organ donors without chronic lung disease and utilized existing single-cell RNA-sequencing (scRNA-seq) data to investigate transcriptional profiles of immune cells over-represented in IPF. Among myeloid cells, we found increased numbers of alveolar macrophages (AMØs) and dendritic cells (DCs) in IPF, as well as a subset of monocyte-derived DC. In contrast, monocyte-like cells and interstitial macrophages were reduced in IPF. Transcriptomic profiling identified an enrichment for interferon-γ (IFN-γ) response pathways in AMØs and DCs from IPF, as well as antigen processing in DCs and phagocytosis in AMØs. Among T cells, we identified three subset of memory T cells that were increased in IPF, including CD4+ and CD8+ resident memory T cells (TRM), and CD8+ effector memory (TEMRA) cells. The response to IFN-γ pathway was enriched in CD4 TRM and CD8 TRM cells in IPF, along with T cell activation and immune response-regulating signaling pathways. Increased AMØs, DCs, and memory T cells were present in IPF lungs compared to control subjects. In IPF, these cells possess an activation profile indicating increased IFN-γ signaling and up-regulation of adaptive immunity in the lungs. Together, these studies highlight critical features of the immunopathogenesis of IPF.

PMID:35468042 | DOI:10.1165/rcmb.2021-0418OC

Comput Struct Biotechnol J. 2022 Mar 31;20:1642-1653. doi: 10.1016/j.csbj.2022.03.030. eCollection 2022.

ABSTRACT

Gefapixant/AF-219, a selective inhibitor of the P2X3 receptor, is the first new drug other than dextromethorphan to be approved for the treatment of refractory chronic cough (RCC) in nearly 60 years. To date, seven P2X subtypes (P2X1-7) activated by extracellular ATP have been cloned, and subtype selectivity of P2X inhibitors is a prerequisite for reducing side effects. We previously identified the site and mechanism of action of Gefapixant/AF-219 on the P2X3 receptor, which occupies a pocket consisting of the left flipper (LF) and lower body (LB) domains. However, the mechanism by which AF-219 selectively acts on the P2X3 receptor is unknown. Here, we combined mutagenesis, chimera construction, molecular simulations, covalent occupation and chemical synthesis, and find that the negative allosteric site of AF-219 at P2X3 is also present in other P2X subtypes, at least for P2X1, P2X2 and P2X4. By constructing each chimera of AF-219 sensitive P2X3 and insensitive P2X2 subtypes, the insensitive P2X2 subtype was made to acquire the inhibitory properties of AF-219 and AF-353, an analog of AF-219 with higher affinity. Our results suggest that the selectivity of AF-219/AF-353 for P2X3 over the other P2X subtypes is determined by a combination of the accessibility of P2X3 binding site and the internal shape of this pocket, a finding that could provide new perspectives for drug design against P2X3-mediated diseases such as RCC, idiopathic pulmonary fibrosis, hypertension and overactive bladder disorder.

PMID:35465163 | PMC:PMC9014320 | DOI:10.1016/j.csbj.2022.03.030

Front Med (Lausanne). 2022 Apr 7;9:889834. doi: 10.3389/fmed.2022.889834. eCollection 2022.

NO ABSTRACT

PMID:35462999 | PMC:PMC9021609 | DOI:10.3389/fmed.2022.889834

BMC Med Imaging. 2022 Apr 23;22(1):76. doi: 10.1186/s12880-022-00803-8.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease that primarily occurs in elderly individuals. However, it is difficult to diagnose and has a complex disease course. High-resolution computed tomography (HRCT) and lung function testing are crucial for its diagnosis and follow-up. However, the correlation of HRCT findings with lung function test results has not been extensively investigated.

METHODS: This study retrospectively analysed the medical records and images of patients with IPF. Patients with evident emphysema and lung cancer were excluded. The diagnosis of all the included cases was confirmed following a discussion among specialists from multiple disciplines. The correlation of HRCT findings, including fibrotic score, HRCT lung volume, pulmonary artery trunk (PA) diameter and pulmonary vascular volume (PVV), with lung function test parameters, such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), was analysed.

RESULTS: A total of 32 patients were included. Higher fibrotic and PVV scores were significantly correlated with lower DLCO (r = - 0.59, p = 0.01; r = - 0.43, p = 0.03, respectively) but not with FVC. Higher PVV score significantly correlated with higher fibrotic score (r = 0.59, p < 0.01) and PA diameter (r = 0.47, p = 0.006).

CONCLUSION: Our study demonstrated the structural and functional correlation of IPF. The extent of lung fibrosis (fibrotic score) and PVV score were associated with DLCO but not with FVC. The PA diameter, which reflects the pulmonary artery pressure, was found to be associated with the PVV score.

PMID:35461214 | DOI:10.1186/s12880-022-00803-8

Respir Res. 2022 Apr 22;23(1):100. doi: 10.1186/s12931-022-02027-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous and fatal lung disease. In addition to dense fibrous tissue, abnormal angiogenesis is also an important feature of IPF. Pigment epithelium-derived factor (PEDF) is an angiogenesis inhibitor and a potential anti-fibrous factor. The purpose of this experiment is to observe the effect of PEDF on bleomycin (BLM)-induced pulmonary fibrosis in rats.

METHODS: In vivo, pathological examination and detection of related factors were performed on pulmonary fibrosis induced by BLM in rats, and the temporal and spatial distribution of PEDF was investigated. Furthermore, lung gene delivery (PEDF-adeno-associated virus) was performed to investigate the effect of PEDF on pulmonary fibrosis. In vitro, lentiviral vectors were used to construct PEDF over-expression or knock out primary rat lung (PRL) fibroblasts. The effect of PEDF on fibroblast activation under TGF-β1 stimulation was evaluated, and the activation of TGF-β1/smad pathway and PPAR-γ expression (in the presence or absence of PPAR-γ inhibitors) were analyzed.

RESULTS: In vivo results showed that PEDF expression decreased during the inflammatory phase and increased during the fibrotic phase. PEDF could inhibit the progression of pulmonary fibrosis in rats. In vitro results showed that PEDF could effectively inhibit TGF-β1-stimulated fibroblast activation and reduce the production of α-SMA and collagen-I. PEDF could inhibit the TGF-β1/smad pathway by up-regulating the activity of PPAR-γ.

CONCLUSIONS: PEDF can act as an anti-fibrotic factor, inhibit fibroblast activation by upregulating PPAR-γ activity and reduce BLM-induced pulmonary fibrosis in rats.

PMID:35459189 | DOI:10.1186/s12931-022-02027-4

BMC Pulm Med. 2022 Apr 23;22(1):153. doi: 10.1186/s12890-022-01953-9.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILDs) include a variety of parenchymal lung diseases. The most common types of ILDs are idiopathic pulmonary fibrosis (IPF), autoimmune ILDs and hypersensitivity pneumonitis (HP). There is limited real world data on care patterns of patients with chronic fibrosing ILDs with a progressive phenotype other than IPF. Therefore, the aim of this study is to describe care patterns in these patients.

METHODS: This retrospective cohort study used claims data from 2015 to 2019 from the Optum Research Database. The study population included adults (≥ 18 years old) with at least two diagnosis codes for fibrosing ILD during the identification period (1OCT2016 to 31DEC2018). A claim-based algorithm for disease progression was used to identify patients likely to have a progressive fibrotic phenotype using progression proxies during the identification period. Index date was the first day of progression proxy identification after fibrosing ILD diagnosis. Patients were required to have continuous enrollment for 12 months before (baseline) and after (follow-up) index date. Patients with an IPF diagnosis were excluded. Descriptive statistics were used to describe the patient population and care patterns.

RESULTS: 11,204 patients were included in the study. Mean age of the patient population was 72.7 years, and 54.5% were female. Unclassified ILDs (48.0%), HP (25.2%) and autoimmune ILDs (16.0%) were the most common ILD types. Other respiratory conditions were prevalent among patients including chronic obstructive pulmonary disease (COPD) (58.9%), obstructive sleep apnea (OSA) (25.0%) and pulmonary hypertension (9.8%). During baseline, 65.3% of all patients had at least one pulmonology visit, this proportion was higher during follow-up, at 70.6%. Baseline and follow-up use for HRCT were 39.9% and 48.8%, and for pulmonary function tests were 43.7% and 48.5% respectively. Use of adrenal corticosteroids was higher during follow-up than during baseline (62.5% vs. 58.0%). Anti-inflammatory and immunosuppressive medication classes were filled by a higher percentage of patients during follow-up than during baseline.

CONCLUSIONS: Comprehensive testing is essential for diagnosis of a progressive phenotype condition, but diagnostic tests were underutilized. Patients with this condition frequently were prescribed anti-inflammatory and immunosuppressive medications.

PMID:35459138 | DOI:10.1186/s12890-022-01953-9

Pharmaceutics. 2022 Apr 7;14(4):813. doi: 10.3390/pharmaceutics14040813.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by irreversible lung scarring, which achieves almost 80% five-year mortality rate. Undeniably, commercially available pharmaceuticals, such as pirfenidone and nintedanib, exhibit certain effects on improving the well-being of IPF patients, but the stubbornly high mortality still indicates a great urgency of developing superior therapeutics against this devastating disease. As an emerging strategy, gene therapy brings hope for the treatment of IPF by precisely regulating the expression of specific genes. However, traditional administration approaches based on viruses severely restrict the clinical application of gene therapy. Nowadays, non-viral vectors are raised as potential strategies for in vivo gene delivery, attributed to their low immunogenicity and excellent biocompatibility. Herein, we highlight a variety of non-viral vectors, such as liposomes, polymers, and proteins/peptides, which are employed in the treatment of IPF. By respectively clarifying the strengths and weaknesses of the above candidates, we would like to summarize the requisite features of vectors for PF gene therapy and provide novel perspectives on design-decisions of the subsequent vectors, hoping to accelerate the bench-to-bedside pace of non-viral gene therapy for IPF in clinical setting.

PMID:35456646 | DOI:10.3390/pharmaceutics14040813

Cells. 2022 Apr 14;11(8):1341. doi: 10.3390/cells11081341.

ABSTRACT

Antibodies are central effectors of the adaptive immune response, widespread used therapeutics, but also potentially disease-causing biomolecules. Antibody folding catalysts in the plasma cell are incompletely defined. Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with increasingly recognized autoimmune features. We found elevated expression of FK506-binding protein 11 (FKBP11) in IPF lungs where FKBP11 specifically localized to antibody-producing plasma cells. Suggesting a general role in plasma cells, plasma cell-specific FKBP11 expression was equally observed in lymphatic tissues, and in vitro B cell to plasma cell differentiation was accompanied by induction of FKBP11 expression. Recombinant human FKBP11 was able to refold IgG antibody in vitro and inhibited by FK506, strongly supporting a function as antibody peptidyl-prolyl cis-trans isomerase. Induction of ER stress in cell lines demonstrated induction of FKBP11 in the context of the unfolded protein response in an X-box-binding protein 1 (XBP1)-dependent manner. While deficiency of FKBP11 increased susceptibility to ER stress-mediated cell death in an alveolar epithelial cell line, FKBP11 knockdown in an antibody-producing hybridoma cell line neither induced cell death nor decreased expression or secretion of IgG antibody. Similarly, antibody secretion by the same hybridoma cell line was not affected by knockdown of the established antibody peptidyl-prolyl isomerase cyclophilin B. The results are consistent with FKBP11 as a novel XBP1-regulated antibody peptidyl-prolyl cis-trans isomerase and indicate significant redundancy in the ER-resident folding machinery of antibody-producing hybridoma cells.

PMID:35456020 | DOI:10.3390/cells11081341

Diagnostics (Basel). 2022 Apr 15;12(4):1002. doi: 10.3390/diagnostics12041002.

ABSTRACT

Antifibrotic therapy has changed the treatment paradigm for idiopathic pulmonary fibrosis (IPF); however, a subset of patients still experienced rapid disease progression despite treatment. This study aimed to determine whether CT-based radiomic features can predict therapeutic response to antifibrotic agents. In this retrospective study, 35 patients with IPF on antifibrotic treatment enrolled from two centers were divided into training (n = 26) and external validation (n = 9) sets. Clinical and pulmonary function data were collected. The patients were categorized into stable disease (SD) and progressive disease (PD) groups based on functional or radiologic criteria. From pretreatment non-enhanced high-resolution CT (HRCT) images, twenty-six radiomic features were extracted through whole-lung texture analysis, and six parenchymal patterns were quantified using dedicated imaging platforms. The predictive factors for PD were determined via univariate and multivariate logistic regression analyses. In the training set (SD/PD: 12/14), univariate analysis identified eight radiomic features and ground-glass opacity percentage (GGO%) as potential predicators of PD. However, multivariate analysis found that the single independent predictor was the sum entropy (accuracy, 80.77%; AUC, 0.75). The combined sum entropy-GGO% model improved the predictive performance in the training set (accuracy, 88.46%; AUC, 0.77). The overall accuracy of the combined model in the validation set (SD/PD: 7/2) was 66.67%. Our preliminary results demonstrated that radiomic features based on pretreatment HRCT could predict the response of patients with IPF to antifibrotic treatment.

PMID:35454050 | DOI:10.3390/diagnostics12041002

Biomedicines. 2022 Apr 5;10(4):851. doi: 10.3390/biomedicines10040851.

ABSTRACT

(1) Background: We explored, for the first time, the contribution of angiogenic T cells (TAng) in interstitial lung disease associated to autoimmune disease (AD-ILD+) as potential biomarkers of the disease, evaluating their role in the underlying vasculopathy and lung fibrosis. Additionally, the relationship of TAng with clinical manifestations and cellular and molecular endothelial dysfunction-related biomarkers was assessed. (2) Methods: We included 57 AD-ILD+ patients (21 with rheumatoid arthritis (RA)-ILD+, 21 with systemic sclerosis (SSc)-ILD+ and 15 with other AD-ILD+) and three comparative groups: 45 AD-ILD- patients (25 RA-ILD- and 20 SSc-ILD-); 21 idiopathic pulmonary fibrosis (IPF) patients; 21 healthy controls (HC). TAng were considered as CD3+CD184+CD31+ by flow cytometry. (3) Results: A similar TAng frequency was found between AD-ILD+ and IPF, being in both cases lower than that observed in AD-ILD- and HC. A lower TAng frequency was associated with negative Scl-70 status and lower FEV1/FVC ratio in SSc-ILD+, as well as with men in RA-ILD+ and non-specific interstitial pneumonia radiological pattern in other AD-ILD+. No relationship between TAng and endothelial progenitor cells, endothelial cells and vascular endothelial growth factor gene expression and protein levels was disclosed. (4) Conclusions: Our findings suggest TAng as potential biomarkers for the early diagnosis of ILD in AD.

PMID:35453601 | DOI:10.3390/biomedicines10040851

Pulm Pharmacol Ther. 2022 Apr 19:102128. doi: 10.1016/j.pupt.2022.102128. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis have a poor overall prognosis and there are few evidence-based drug therapies that reduce mortality.

OBJECTIVE: We aimed to perform a systematic review and meta-analysis to assess whether sildenafil reduces mortality, disease progression and adverse side effects.

METHODS: We reviewed randomized controlled studies (RCTs) from MEDLINE, Cochrane registry of clinical trials, and EMBASE. Our outcomes of interest included mortality, change in FVC, acute exacerbations and hospitalizations and adverse drug effects leading to discontinuation. We used an inverse variance fixed effects meta-analysis method to calculate pooled relative risk (RR) and mean difference (MD).

RESULTS: A total of 4 studies were included in the systematic review. Sildenafil probably reduces mortality when compared to placebo or to standard care, [RR 0.73 (95% CI 0.51 to 1.04); moderate certainty]. Pooled estimates showed sildenafil may not alter the rate of change of FVC [MD 0.61% (95% CI -0.29 to 1.52)], or DLCO [MD 0.97% (95% CI 0.04 to 1.90)] (both low certainty). Pooled estimated showed sildenafil may not reduce the number of hospitalizations or acute exacerbations, [RR 1.10 (95% CI 0.61 to 1.98); low certainty]. There is probably no difference in drug discontinuation due to adverse effects when comparing sildenafil to the control group, [RR 0.79 (95% CI 0.56, 1.10); moderate certainty].

CONCLUSION: Sildenafil probably reduces all-cause mortality in IPF patients. More studies need to be done to confirm the magnitude and reliability of the point estimate.

PMID:35452834 | DOI:10.1016/j.pupt.2022.102128

J Drug Target. 2022 Apr 22:1-11. doi: 10.1080/1061186X.2022.2069781. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by irreversible fibrosis and destruction of the alveolar structure. Receptor for advanced glycation end-products (RAGE) has been identified as one of the key molecules involved in IPF pathogenesis. A RAGE antagonist peptide (RAP) was developed based on the RAGE-binding domain of high mobility group box-1 (HMGB-1). Anti-IPF effects of RAP were evaluated in a bleomycin-induced mouse model of IPF. Bleomycin was administered intratracheally, and then RAP was administrated twice by intratracheal instillation, 1 and 3 days after bleomycin challenge. Seven days after the bleomycin challenge, the mice were sacrificed and the lungs were harvested. The results showed that pulmonary hydroxyproline was reduced in mice administered RAP compared with the control group. Tumor growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), and collagen were also reduced by RAP administration in a dose-dependent manner. Longer-term effects of RAP were investigated in mice challenged with bleomycin. RAP was administered intratracheally every 7 days for 28 days, after which lung samples were harvested and analyzed. The results showed that hydroxyproline, TGF-β, α-SMA, and collagen were reduced by repeated RAP administration. Taken together, the results suggest that RAP is useful for treatment of IPF.

PMID:35451894 | DOI:10.1080/1061186X.2022.2069781

Thorac Cancer. 2022 Apr 22. doi: 10.1111/1759-7714.14418. Online ahead of print.

ABSTRACT

OBJECTIVES: Whether curative-intent radiotherapy could be safely applied to lung cancer patients with interstitial lung diseases (ILD) remains unclear. We aim to evaluate radiation induced lung toxicities (RILTs) and the efficacy of intensity-modulated radiotherapy (IMRT) in these patients. ILD is characterized by inflammation or fibrosis in the interstitial tissue of the lung.

MATERIALS AND METHODS: Stage III non-small cell lung cancer (NSCLC) and ILD patients treated with curative-intent IMRT between 2010 and 2019 were retrospectively reviewed. Pre-radiation computed tomography (CT) was scored according to a thin-section CT scoring system for idiopathic pulmonary fibrosis.

RESULTS: A total of 85 of 1261 stage III NSCLC patients were found with ILD. Seventeen (20%) of them developed G3+ (greater than or equal to grade 3) RILTs. The incidence abruptly dropped to 11.1%, 3.8%, and 0% for patients with honeycombing score ≤1, V20 <20%, or both, respectively. Multivariate analysis showed that honeycombing score >1 and V20 ≥20% were independently associated with higher risk of G3+ RILTs. The median overall survival (OS) and progression-free survival (PFS) were 14.0 months and 7.4 months in the whole group, whereas 26.5 months and 10.6 months in the low-risk group (patients with honeycombing score <1 and V20 <20%). In the univariate analysis for overall survival, G3+ RILTs were evaluated as risk factors (p = 0.026) and low-risk group as the only protective factor (p = 0.063). In the multivariate analysis, G3+ RILTs were the only independent risk factor for OS.

CONCLUSION: Honeycombing score >1 and V20 ≥20% were associated with high incidence of RILTs. However, patients with low risk might benefit from IMRT with acceptable toxicities and durable OS.

PMID:35451221 | DOI:10.1111/1759-7714.14418

Ann Dermatol. 2022 Apr;34(2):136-138. doi: 10.5021/ad.2022.34.2.136. Epub 2022 Mar 24.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal lung disease characterized by progressive dyspnea and irreversible loss of lung function. Pirfenidone is a novel anti-fibrotic and anti-inflammatory drug, which reduces deterioration in the lung function and prolongs progression-free survival in patients with IPF. However, it has adverse effects including gastrointestinal symptoms, hepatic dysfunction or skin photosensitivity, and rash. Lichenoid drug eruption (LDE) refers to lichen planus-like drug eruption usually presenting symmetric eczematous plaques with a purple hue. To date, numerous cases of LDE due to various drugs and pirfenidone-associated photosensitivity have been reported. However, a case of pirfenidone-induced LDE has been very rarely reported to our knowledge. Herein, is a case of pirfenidone-induced LDE so that clinicians can be aware of the possibility of LDE when using pirfenidone.

PMID:35450308 | PMC:PMC8989899 | DOI:10.5021/ad.2022.34.2.136

Respir Res. 2022 Apr 21;23(1):97. doi: 10.1186/s12931-022-02013-w.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF.

METHODS: We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets.

RESULTS: We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts.

CONCLUSIONS: We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF.

PMID:35449067 | DOI:10.1186/s12931-022-02013-w

Am J Respir Crit Care Med. 2022 Apr 21. doi: 10.1164/rccm.202203-0474ED. Online ahead of print.

NO ABSTRACT

PMID:35446243 | DOI:10.1164/rccm.202203-0474ED

Am J Respir Crit Care Med. 2022 Apr 21. doi: 10.1164/rccm.202111-2590LE. Online ahead of print.

NO ABSTRACT

PMID:35446241 | DOI:10.1164/rccm.202111-2590LE

Am J Respir Crit Care Med. 2022 Apr 21. doi: 10.1164/rccm.202109-2219PP. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the cumulative manifestation of countless, spatially and temporally distinct, microscopic foci of maladaptive repair in response to recurrent lung injury. However, the key drivers, essential cells, and critical mechanisms of maladaptive repair in IPF remain elusive. Decades of research have focused on alveolar injury and alveolar-mesenchymal crosstalk with their association to type II alveolar epithelial defects, fibroblast activation, and progressive lung fibrosis resulting in diminished organ function. Additionally, it has been well documented that immune and endothelial cell-types are involved in IPF. However, the airway epithelium has been incompletely described in IPF, even with significant evidence of airway-specific involvement. One of the first descriptions of distal airway dysfunction in IPF was over four-decades ago; however, since this discovery, our understanding of distal airway epithelial contributions to IPF pathogenesis has not kept pace with other tissues-types or anatomical regions of the lung. Healthy distal, which is defined here as an airway < 2 mm in internal diameter, airway epithelium is composed primarily of progenitor, mucus-producing, and multiciliated cell populations. Large increases in progenitor population diversity, misexpression of mucus, and possible aberrant ciliation observed in IPF has reinvigorated interest in the distal airway epithelium.

PMID:35446237 | DOI:10.1164/rccm.202109-2219PP

Int J Epidemiol. 2022 Apr 20:dyac076. doi: 10.1093/ije/dyac076. Online ahead of print.

ABSTRACT

BACKGROUND: To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies.

METHODS: In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses.

RESULTS: We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2'-5' oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk.

CONCLUSION: This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19.

PMID:35445260 | DOI:10.1093/ije/dyac076