Respir Res. 2021 Apr 20;22(1):115. doi: 10.1186/s12931-021-01726-8.

ABSTRACT

BACKGROUND: Idiopathic non-specific interstitial pneumonia (iNSIP), idiopathic pleuroparenchymal fibroelastosis (iPPFE), and unclassifiable idiopathic interstitial pneumonia (IIP) are IIPs with chronic fibrotic phenotypes, and unlike idiopathic pulmonary fibrosis, they have often been treated with anti-inflammatory drugs, including corticosteroids and immunosuppressants. However, the impact of bronchoalveolar lavage (BAL) lymphocytosis on the effects of anti-inflammatory therapy has never been evaluated. This study aimed to elucidate whether BAL lymphocytosis can be used to predict the efficacy of anti-inflammatory drugs for iNSIP, iPPFE, and unclassifiable IIP.

METHODS: Japanese patients diagnosed with iNSIP, iPPFE, and unclassifiable IIP by multidisciplinary discussion were identified using the nationwide registry. Eligible patients were stratified into four groups with and without BAL lymphocytosis and anti-inflammatory therapy to compare overall survival (OS) and changes in lung function. BAL lymphocytosis was defined as a lymphocyte differential count > 15%, and the cut-off was corroborated by survival classification and regression tree analysis.

RESULTS: Overall, 186 patients (37 iNSIP, 16 iPPFE, and 133 unclassifiable IIP) were analyzed. Limited to patients treated with anti-inflammatory drugs (n = 123), patients with BAL lymphocytosis had a better prognosis [hazard ratio (HR), 0.26; 95% confidence interval (CI), 0.11-0.63; P = 0.003], higher slope of forced vital capacity (FVC) % predicted for 2 years, and longer OS (log-rank test, P = 0.012) than those without BAL lymphocytosis. On multivariate analysis, BAL lymphocytosis (HR 0.31; 95% CI 0.13-0.75; P = 0.009) was a prognostic factor for OS, along with age and FVC % predicted. Conversely, for patients managed without anti-inflammatory therapy (n = 63), the presence or absence of BAL lymphocytosis had no prognostic value.

CONCLUSIONS: BAL lymphocytosis is associated with good outcomes in patients treated with anti-inflammatory drugs, but has no prognostic value when anti-inflammatory drugs are not used. BAL lymphocytosis may provide a predictive biomarker for identifying patients with iNSIP, iPPFE and unclassifiable IIP who are likely to benefit from anti-inflammatory drugs.

PMID:33879137 | DOI:10.1186/s12931-021-01726-8

J Pharm Pract. 2021 Apr 21:8971900211008625. doi: 10.1177/08971900211008625. Online ahead of print.

ABSTRACT

BACKGROUND: In the treatment of idiopathic pulmonary fibrosis (IPF), nintedanib and pirfenidone, with their different mechanisms of action, lead to a reduction in the rate of progression of the fibrosis process measured by the reduction of functional decline, and, in particular, the decrease in forced vital capacity (FVC) and of the diffusion capacity of the lungs for carbon monoxide (DLCO). The objective of this study was to analyze real-life adherence, persistence and efficacy in the use of pirfenidone and nintedanib in the treatment of IPF.

METHODS: A non-interventional multicenter retrospective observational pharmacological study in real-life treat-ment at 1 and 2 years was conducted. Furthermore, we analyzed the levels of FVC and DLCO at 6 and 12 months, respectively, from the start of treatment.

RESULTS: We identified 144 patients in the period between January 2013 and April 2019. From the point of view of adherence, there is no difference between the two drugs, even though patients who used pirfenidone had increasingly higher values: 0.90 vs 0.89, in the first year, and 0.91 vs 0.84, in the second year. In the first year of treatment, the percentage of persistent patients was 67% and 76%, while in the second year, it dropped to 47% and 53% for pirfenidone and nintedanib, respectively.

CONCLUSION: The stratification of the adherence values as a function of the response to treatment in terms of FVC at 12 months for both study drugs showed that patients with optimal response scored adherence of more than 90%.

PMID:33878986 | DOI:10.1177/08971900211008625

Ther Adv Respir Dis. 2021 Jan-Dec;15:1753466621995045. doi: 10.1177/1753466621995045.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare form of immune-mediated interstitial lung disease characterized by progressive pulmonary fibrosis and scarring. The pathogenesis of IPF is still unclear. Gene fusion events exist universally during transcription and show alternated patterns in a variety of lung diseases. Therefore, the comprehension of the function of gene fusion in IPF might shed light on IPF pathogenesis research and facilitate treatment development.

METHODS: In this study, we included 91 transcriptome datasets from the National Center for Biotechnology Information (NCBI), including 52 IPF patients and 39 healthy controls. We detected fusion events in these datasets and probed gene fusion-associated differential gene expression and functional pathways. To obtain robust results, we corrected the batch bias across different projects.

RESULTS: We identified 1550 gene fusion events in all transcriptomes and studied the possible impacts of IL7 = AC083837.1 gene fusion. The two genes locate adjacently in chromosome 8 and share the same promoters. Their fusion is associated with differential expression of 282 genes enriched in six Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and 35 functional gene sets. Gene ontology (GO) enrichment analysis shows that IL7 = AC083837.1 gene fusion is associated with the enrichment of 187 gene sets. The co-expression network of interleukin-7 (IL7) indicates that decreased IL7 expression is associated with many pathways that regulate IPF progress.

CONCLUSION: Based on the results, we conclude that IL7 = AC083837.1 gene fusion might exacerbate fibrosis in IPF via enhancing activities of natural killer cell-mediated cytotoxicity, skin cell apoptosis, and vessel angiogenesis, the interaction of which contributes to the development of fibrosis and the deterioration of respiratory function of IPF patients. Our work unveils the possible roles of gene fusion in regulating IPF and demonstrates that gene fusion investigation is a valid approach in probing immunologic mechanisms and searching potential therapeutic targets for treating IPF.The reviews of this paper are available via the supplemental material section.

PMID:33878985 | DOI:10.1177/1753466621995045

Respirology. 2021 Apr 19. doi: 10.1111/resp.14066. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Physical frailty is associated with increased mortality and hospitalizations in older adults. We describe the prevalence of physical frailty and its prognostic impact in patients with a spectrum of fibrotic interstitial lung disease (ILD).

METHODS: Patients with fibrotic ILD at the McMaster University ILD programme were prospectively followed up from November 2015 to March 2020. Baseline data were used to classify patients as non-frail (score = 0), pre-frail (score = 1-2) or frail (score = 3-5) based on modified Fried physical frailty criteria. The association between physical frailty and mortality was assessed using time-to-event models, adjusted for age, sex, lung function and diagnosis using the ILD Gender-Age-Physiology (ILD-GAP) score.

RESULTS: We included 463 patients (55% male, mean [SD] age 68 [11] years); 82 (18%) were non-frail, 258 (56%) pre-frail and 123 (26%) frail. The most common ILD diagnoses were idiopathic pulmonary fibrosis (n = 183, 40%) and connective tissue disease-associated-ILD (n = 79, 17%). Mean time since diagnosis was 2.7 ± 4.6 years. There were 56 deaths within the median follow-up of 1.71 (interquartile range [IQR] 1.24, 2.31) years. Both frail and pre-frail individuals had a higher risk of death compared to those categorized as non-frail at baseline (adjusted hazard ratio [aHR] 4.14, 95% CI 1.27-13.5 for pre-frail and aHR 4.41, 95% CI 1.29-15.1 for frail).

CONCLUSION: Physical frailty is prevalent in patients with ILD and is independently associated with an increased risk of death. Assessment of physical frailty provides additional prognostic value to recognized risk scores such as the ILD-GAP score, and may present a modifiable target for intervention.

PMID:33876511 | DOI:10.1111/resp.14066

Respiration. 2021 Apr 19:1-12. doi: 10.1159/000515396. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The research term "interstitial pneumonia with autoimmune features" (IPAF) encompasses interstitial lung disease (ILD) patients with autoimmune features not meeting diagnostic criteria for a defined connective tissue disease (CTD). It remains unclear if IPAF is a distinct disease entity with implications for management and prognosis. We describe an Australian IPAF population and compare their baseline characteristics and outcomes with distinct cohorts of idiopathic interstitial pneumonia (IIP), CTD-ILD, and unclassifiable ILD.

METHODS: Review of 291 consecutive patients attending a specialist ILD clinic was performed. Patients with a diagnosis of IIP, CTD-ILD, and unclassifiable ILD by ILD-multidisciplinary meeting (ILD-MDM) were included. Patients meeting the IPAF criteria were identified. Baseline clinical data, survival, and progression were compared between ILD groups.

RESULTS: 226 patients were included, 36 meeting the IPAF criteria. IPAF patients demonstrated a high prevalence of autoantibodies to tRNA synthetase (35.3%), Ro52 (27.8%), and neutrophilic cytoplasmic antigens (ANCA; 20.0%). IPAF and CTD-ILD patients demonstrated similar clinical characteristics (mean age 66.6 and 63.7 years, respectively, female predominant, frequent CTD-manifestations). Lung function did not differ between ILD groups. Disease severity, pulmonary hypertension (PH), and ILD-MDM diagnosis were strong predictors of worse transplant-free survival (TFS). Meeting the IPAF criteria was not associated with TFS.

CONCLUSIONS: We identified IPAF as a heterogeneous phenotype that overlaps considerably with CTD-ILD. Disease severity, PH, and ILD-MDM diagnosis were more powerful predictors of survival outcomes than meeting the IPAF criteria.

PMID:33873185 | DOI:10.1159/000515396

Turk Thorac J. 2021 Mar;22(2):102-109. doi: 10.5152/TurkThoracJ.2021.20028. Epub 2021 Mar 1.

ABSTRACT

OBJECTIVE: Differential diagnosis of idiopathic pulmonary fibrosis (IPF) is important among fibrotic interstitial lung diseases (ILD). This study aimed to evaluate the rate of IPF in patients with fibrotic ILD and to determine the clinical-laboratory features of patients with and without IPF that would provide the differential diagnosis of IPF.

MATERIAL AND METHODS: The study included the patients with the usual interstitial pneumonia (UIP) pattern or possible UIP pattern on thorax high-resolution computed tomography, and/or UIP pattern, probable UIP or possible UIP pattern at lung biopsy according to the 2011 ATS/ERS/JRS/ALAT guidelines. Demographics and clinical and radiological data of the patients were recorded. All data recorded by researchers was evaluated by radiology and the clinical decision board.

RESULTS: A total of 336 patients (253 men, 83 women, age 65.8±9.0 years) were evaluated. Of the patients with sufficient data for diagnosis (n=300), the diagnosis was IPF in 121 (40.3%), unclassified idiopathic interstitial pneumonia in 50 (16.7%), combined pulmonary fibrosis and emphysema (CPFE) in 40 (13.3%), and lung involvement of connective tissue disease (CTD) in 16 (5.3%). When 29 patients with definite IPF features were added to the patients with CPFE, the total number of IPF patients reached 150 (50%). Rate of male sex (p<0.001), smoking history (p<0.001), and the presence of clubbing (p=0.001) were significantly high in patients with IPF. None of the women <50 years and none of the men <50 years of age without a smoking history were diagnosed with IPF. Presence of at least 1 of the symptoms suggestive of CTD, erythrocyte sedimentation rate (ESR), and antinuclear antibody (FANA) positivity rates were significantly higher in the non-IPF group (p<0.001, p=0.029, p=0.009, respectively).

CONCLUSION: The rate of IPF among patients with fibrotic ILD was 50%. In the differential diagnosis of IPF, sex, smoking habits, and the presence of clubbing are important. The presence of symptoms related to CTD, ESR elevation, and FANA positivity reduce the likelihood of IPF.

PMID:33871332 | DOI:10.5152/TurkThoracJ.2021.20028

J Interprof Care. 2021 Apr 17:1-11. doi: 10.1080/13561820.2021.1884051. Online ahead of print.

ABSTRACT

Descriptions of how to foster and accomplish interprofessional collaboration (IPC) in practice across different healthcare settings are needed. This paper examines the transformation of a normative interstitial lung disease (ILD) clinic to an IPC delivering person-centric care across an outpatient specialty clinic and the community. It describes how the IPC was started; the actions undertaken to do this; and the processes supporting it within the outpatient clinic, and between it and its community-based partners. Qualitative research methods (participants-as-co-researchers, unstructured interviews, thematic content analysis) were used with the two physicians founding the IPC to understand this transformation process; this is supplemented with preliminary findings of interviews with patients/carers (N = 30) attending the outpatient clinic. Analysis suggests the power of IPC to improve patients' quality of life and death, reduce acute care use and hospitalization, and realize patient preferences for location of death. Despite this, the ILD IPC encounters resistance from larger institutional and political forces.

PMID:33870830 | DOI:10.1080/13561820.2021.1884051

Respirology. 2021 Apr 18. doi: 10.1111/resp.14044. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Patients with idiopathic pulmonary fibrosis (IPF) often develop postoperative severe respiratory complications such as acute exacerbation. Pirfenidone, an oral anti-fibrotic drug, may reduce the incidence of such complications. However, the preventive effect of pirfenidone on postoperative severe respiratory complications remains unclear.

METHODS: We identified patients with IPF who underwent surgery with general anaesthesia from July 2010 to March 2018 using the Diagnosis Procedure Combination database. We compared the occurrence of postoperative severe respiratory complications (receiving mechanical ventilation under endotracheal intubation and/or intravenous infusion of a high-dose corticosteroid and in-hospital death within 30 days after surgery) between patients who did and did not receive preoperative treatment with pirfenidone. Pearson's chi-square test and logistic regression analysis fitted with a generalized estimating equation were conducted in 1:4 propensity score-matched patients.

RESULTS: Among 631 patients identified, 19% were treated with pirfenidone before surgery. The 30-day mortality rate was 3.1% and 1.7% in the control patients (n = 510) and pirfenidone-treated patients (n = 121), respectively. In the propensity score-matched population, preoperative treatment with pirfenidone was significantly associated with a lower proportion of postoperative severe respiratory complications (OR: 0.24; 95% CI: 0.07-0.76; p = 0.015).

CONCLUSION: In this Japanese nationwide cohort, preoperative treatment with pirfenidone was significantly associated with a lower risk of postoperative severe respiratory complications in patients with IPF. Preoperative pirfenidone may thus be useful in preventing postoperative severe respiratory complications in patients with IPF who are planning to undergo surgery with general anaesthesia.

PMID:33870611 | DOI:10.1111/resp.14044

Front Mol Biosci. 2021 Mar 31;8:660800. doi: 10.3389/fmolb.2021.660800. eCollection 2021.

ABSTRACT

BACKGROUND AND OBJECTIVE: Interstitial lung disease with lung cancer (ILD-LC) is rare and its management has not been fully described. This study aimed to investigate the management and prognosis of ILD-LC patients in China.

METHODS: The present analysis is a retrospective real-world cohort study. Clinical data of ILD-LC patients were obtained from 3 hospitals in China. The overall survival (OS) of patients was analyzed. Univariate and multivariate regression analyses were performed.

RESULTS: One hundred eighty-four ILD-LC patients included were biased toward male (85.3%), smokers (75.5%), idiopathic pulmonary fibrosis (IPF) (58.2%) patients with comorbidities (67.9%) and ECOG-PS score of 1 (65.2%). Most patients were advanced peripheral non-small cell lung cancer. The initial anti-cancer regimen for ILD-LC is mainly chemotherapy, and patients with early-stage LC prefer surgery. In the anti-cancer cohort, the number of ILD-LC patients who underwent the 2nd and 3rd or more anti-cancer regimens were 78 (55.7%) and 32 (22.8%), respectively. In the non-anticancer cohort, the median OS was 3.5 months. In the early-stage cohort, the median OS was 14.2 months in the systematic therapy group; however, the median OS was not reached in the surgery group. In the advanced-stage cohort with systematic therapy, the median OS was 7.2 months. Interstitial pneumonia (IIP) and anti-angiogenesis were associated with OS in the univariate analysis, whereas anti-angiogenesis was an independent protective factor for advanced LC with ILD.

CONCLUSION: Patients with ILD-LC have very poor prognosis. Appropriate anti-tumor treatment can prolong the survival time of patients who can tolerate it. Targeted therapy and immunotherapy are alternative treatments for LC patients with mild ILD. For ILD patients with advanced LC, antiangiogenic regimens significantly improve the prognosis of the disease.

PMID:33869290 | PMC:PMC8044367 | DOI:10.3389/fmolb.2021.660800

Pulm Circ. 2021 Mar 30;11(2):2045894021999960. doi: 10.1177/2045894021999960. eCollection 2021 Apr-Jun.

ABSTRACT

The implications of the recent change in the definition of pulmonary hypertension on epidemiology and outcomes are not known. We sought to determine the percentage of patients with the two most common lung diseases that would be reclassified regarding the presence/absence of pulmonary hypertension with the revised definition. A query of the United Network for Organ Sharing database was performed. The percentage of patients meeting the current and previous definition of pulmonary hypertension was described. Outcomes of patients stratified by the current and previous definitions were compared. There were 15,563 patients with right heart catheterization data analyzed. Pulmonary hypertension was more prevalent in both chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis under the new definition at 52.4% versus 82.4%, and 47.6% versus 73.6%, respectively. "Pre-capillary" pulmonary hypertension by the new definition was lower at 28.1% for chronic obstructive pulmonary disease and 36.8% for idiopathic pulmonary fibrosis. Of the patients with pulmonary hypertension by the old definition, 23.9% of chronic obstructive pulmonary disease patients and 18.7% of idiopathic pulmonary fibrosis patients were not classified as pulmonary hypertension by the new definition. Conversely, 15.9% of chronic obstructive pulmonary disease patients and 15.1% of idiopathic pulmonary fibrosis patients who did not meet diagnostic criteria for pulmonary hypertension by the old definition did have pulmonary hypertension by the new definition. Patients in both disease categories had shorter transplant-free waitlist survival in the presence of pulmonary hypertension by both the new and old definitions. There was a trend toward the new definition of pre-capillary pulmonary hypertension better discerning outcomes compared to the old definition of pulmonary hypertension in idiopathic pulmonary fibrosis patients. Most patients with advanced lung disease who are listed for lung transplantation have pulmonary hypertension, but fewer have pre-capillary pulmonary hypertension than pulmonary hypertension by the old definition. Both the old and new definition of precapillary pulmonary hypertension appear to discern outcomes among the two groups of lung disease analyzed, with some evidence to suggest that the new definition performs slightly better in the idiopathic pulmonary fibrosis population.

PMID:33868639 | PMC:PMC8020109 | DOI:10.1177/2045894021999960

Sarcoidosis Vasc Diffuse Lung Dis. 2021;38(1):e2021012. doi: 10.36141/svdld.v38i1.9734. Epub 2021 Mar 31.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) of interstitial pneumonia (IP) occurs commonly and has a poor prognosis. Polymyxin B hemoperfusion (PMX-DHP) has a beneficial effect on AE of some types of IPs, particularly idiopathic pulmonary fibrosis (IPF). However, little is known about the efficacy of PMX-DHP in the Korean population. The aim of this study was to examine the effectiveness of PMX-DHP in AE of IP.

METHODS: We conducted a retrospective study of 12 patients with AE of IP, including two patients with AE of IPF, who were treated with PMX-DHP at our center. Treatment with PMX-DHP was carried out once or twice. We collected and analyzed data on changes in oxygenation with PMX-DHP and survival after AE.

RESULTS: In patients with AE of IP, the ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, or the P/F ratio, had significantly improved at the end of the treatment with PMX-DHP (87.0 [80.3 - 130.9] to 200.6 [105.0 - 245.5] mmHg, p = 0.019). The white blood cell (WBC) count had significantly reduced at the end of the treatment (12,400 [8,860 - 20,287] to 6,800 [3,950 - 15,775]/mm3, p = 0.050). The 28-day and in-hospital mortality rates of patients after AE of IP were 41.7 % and 75.0 %, respectively.

CONCLUSION: PMX-DHP improved oxygenation and reduced the WBC count in patients with AE, with either steroids alone or steroids and cyclophosphamide. Further studies are required to verify the potential benefits of PMX-DHP for patients with AE of IP.

PMID:33867795 | PMC:PMC8050624 | DOI:10.36141/svdld.v38i1.9734

Sarcoidosis Vasc Diffuse Lung Dis. 2021;38(1):e2021005. doi: 10.36141/svdld.v38i1.9258. Epub 2021 Mar 31.

ABSTRACT

BACKGROUND: The six-minute walk test (6MWT) is a readily available tool used to evaluate functional capacity in patients with idiopathic pulmonary fibrosis (IPF). However, it is often logistically challenging to perform in the context of a busy clinical practice. We sought to investigate if the 1MWT distance (1MWD) predicts the 6MWT distance (6MWD), and if an abbreviated walk could accurately predict outcomes in IPF patients.

METHODS: Baseline demographics and pulmonary function testing of IPF patients evaluated at a tertiary referral center between 2010 and 2017 were collected. 6MWT variables at baseline as well as 1 and 6 minutes were collected. Time to death, lung transplantation, or most recent follow-up was ascertained.

RESULTS: There were 177 patients, the majority of whom (80%) were male. The mean age was 67 ± 9 years and mean FVC was 64 ± 18% predicted. Forty eight (27%) patients used oxygen supplementation during the 6MWT. The median 6MWD was 366 meters (IQR: 268-471) while the median 1MWD was 65 meters (IQR: 46-81). Stratified by the median, 89 patients were "High Walkers" based on the 6MWD ≥ 366m (HW6) and 88 patients were "Low Walkers" (LW6). HW6 had a higher FVC% (70 ± 15 vs 57 ± 18, p= 0.001), higher DLCO% (45 ± 12 vs 34 ± 14, p= 0.001) and higher 1MWD (83 ± 28 vs 47 ± 16, m p= 0.001). Median transplant-free survival was better in HW6 vs LW6 (27 ± 16 vs 22 ± 18 months, log rank p= 0.018). There was a strong correlation between the 1MWD and the 6MWD (r= 0.91, Spearman's correlation, p < 0.0001). Also, the transplant-free survival curves stratified by 1MWD were very similar to the curves for 6MWD, showing a lower survival in the LW1 cohort (log rank p= 0.009).

CONCLUSION: The 1MWD obtained during the first minute of a 6MWD shows a strong correlation to total 6MWD and retains its ability to predict transplant-free survival. 1MWT may serve as a practical substitute for the more cumbersome 6MWT. Our findings require further validation prospectively in larger cohorts of IPF patients.

PMID:33867792 | PMC:PMC8050623 | DOI:10.36141/svdld.v38i1.9258

Respir Res. 2021 Apr 17;22(1):109. doi: 10.1186/s12931-021-01711-1.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with an estimated median survival time of 3-5 years after diagnosis. This condition occurs primarily in elderly subjects, and epidemiological studies suggest that the main risk factors, ageing and exposure to cigarette smoke, are associated with both pulmonary and extrapulmonary comorbidities (defined as the occurrence of two or more disorders in a single individual). Ageing and senescence, through interactions with environmental factors, may contribute to the pathogenesis of IPF by various mechanisms, causing lung epithelium damage and increasing the resistance of myofibroblasts to apoptosis, eventually resulting in extracellular matrix accumulation and pulmonary fibrosis. As a paradigm, syndromes featuring short telomeres represent archetypal premature ageing syndromes and are often associated with pulmonary fibrosis. The pathophysiological features induced by ageing and senescence in patients with IPF may translate to pulmonary and extrapulmonary features, including emphysema, pulmonary hypertension, lung cancer, coronary artery disease, gastro-oesophageal reflux, diabetes mellitus and many other chronic diseases, which may lead to substantial negative consequences in terms of various outcome parameters in IPF. Therefore, the careful diagnosis and treatment of comorbidities may represent an outstanding chance to improve quality of life and survival, and it is necessary to contemplate all possible management options for IPF, including early identification and treatment of comorbidities.

PMID:33865386 | DOI:10.1186/s12931-021-01711-1

Cell Mol Life Sci. 2021 Apr 17. doi: 10.1007/s00018-021-03841-7. Online ahead of print.

ABSTRACT

Mammalian lungs are metabolically active organs that frequently encounter environmental insults. Stress responses elicit protective autophagy in epithelial barrier cells and the supportive niche. Autophagy promotes the recycling of damaged intracellular organelles, denatured proteins, and other biological macromolecules for reuse as components required for lung cell survival. Autophagy, usually induced by metabolic defects, regulates cellular metabolism. Autophagy is a major adaptive response that protects cells and organisms from injury. Endogenous region-specific stem/progenitor cell populations are found in lung tissue, which are responsible for epithelial repair after lung damage. Additionally, glucose and fatty acid metabolism is altered in lung stem/progenitor cells in response to injury-related lung fibrosis. Autophagy deregulation has been observed to be involved in the development and progression of other respiratory diseases. This review explores the role and mechanisms of autophagy in regulating lung metabolism and epithelial repair.

PMID:33864479 | DOI:10.1007/s00018-021-03841-7

EBioMedicine. 2021 Apr 13;66:103325. doi: 10.1016/j.ebiom.2021.103325. Online ahead of print.

ABSTRACT

BACKGROUND: The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition.

METHODS: Pre-operative thoracic Multidetector Computed Tomography (MDCT) scans of patients with severe IPF (n = 9) were used to identify regions of minimal(n = 27) and established fibrosis(n = 27). MDCT, Micro-CT, quantitative histology, and next-generation sequencing were used to compare 24 samples from donor controls (n = 4) to minimal and established fibrosis samples.

FINDINGS: The present results extended earlier reports about the transition from normal lung anatomy to minimal and established fibrosis by showing that there are activations of TGFBI, T cell co-stimulatory genes, and the down-regulation of inhibitory immune-checkpoint genes compared to controls. The expression patterns of these genes indicated activation of a field immune response, which is further supported by the increased infiltration of inflammatory immune cells dominated by lymphocytes that are capable of forming lymphoid follicles. Moreover, fibrosis pathways, mucin secretion, surfactant, TLRs, and cytokine storm-related genes also participate in the transitions from normal lung anatomy to minimal and established fibrosis.

INTERPRETATION: The transition from normal lung anatomy to minimal and established fibrosis is associated with genes that are involved in the tissue repair processes, the activation of immune responses as well as the increased infiltration of CD4, CD8, B cell lymphocytes, and macrophages. These molecular and cellular events correlate with the development of structural abnormality of IPF and probably contribute to its pathogenesis.

PMID:33862585 | DOI:10.1016/j.ebiom.2021.103325

Am J Respir Cell Mol Biol. 2021 Apr 16. doi: 10.1165/rcmb.2020-0279OC. Online ahead of print.

ABSTRACT

Strict control of iron homeostasis is critical for the maintenance of normal lung function. Iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (IPF), but the characteristics of iron metabolism in the pathogenesis of pulmonary fibrosis (PF) and related targeting therapeutics are not well studied. In this study, we investigated the cellular and molecular characteristics of iron metabolism in fibrotic lungs and further explored the efficacy of clioquinol (CQ) for the treatment of PF as well as its functional mechanism. Iron aggregates accumulated in the lungs of patients with IPF, and ferritin light chain (FTL) transcripts were increased in their pulmonary fibroblasts. In the bleomycin (BLM)-induced pulmonary fibrosis (BLM-PF) mouse model, pulmonary iron accumulation is a very early and concomitant event of PF. Labile iron pool (LIP) levels in both fibroblasts and macrophages from the BLM-PF model were elevated, and iron metabolism was dysregulated. CQ attenuated PF induced by BLM and fluorescein isothiocyanate (FITC), and iron-saturated clioquinol (ISCQ) did not alleviate BLM-PF. Furthermore, CQ inhibited the activation of fibroblasts, including proliferation, fibrotic differentiation, proinflammatory cytokine secretion and migration. In conclusion, our study demonstrated that CQ, acting as an iron chelator, attenuates experimental PF through inactivation of fibroblasts, providing support for targeting iron metabolism as a basis for PF treatment.

PMID:33861690 | DOI:10.1165/rcmb.2020-0279OC

Front Immunol. 2021 Mar 30;12:595811. doi: 10.3389/fimmu.2021.595811. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1 hi and FABP4 hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.

PMID:33859634 | PMC:PMC8042271 | DOI:10.3389/fimmu.2021.595811

Sci Rep. 2021 Apr 15;11(1):8312. doi: 10.1038/s41598-021-87747-1.

ABSTRACT

The clinical characteristics of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) differ from those of lung cancer in patients without IPF. Thus, we aimed to evaluate the impact of IPF on the clinical course of patients with lung cancer. Clinical data of IPF patients with lung cancer (n = 122) were compared with those of patients with lung cancer without IPF (n = 488) matched by age, sex, histopathology, stage, and date of diagnosis of lung cancer. The median follow-up period after diagnosis of lung cancer was 16 months. Among patients with IPF, the mean age was 68 years, 95.9% were male, 93.2% were ever-smokers, and squamous cell carcinoma was the most common cancer type (48.4%). The IPF group had poorer lung function and lower lobe predominance of lung cancer than the no-IPF group. The IPF group showed a poorer prognosis than the no-IPF group (5-year survival rate: 14.5% vs. 30.1%, respectively; P < 0.001), even after adjusting for lung function and regardless of the treatment method. Among patients with IPF, 16.8% experienced acute exacerbation within 1 month after treatment of lung cancer. The treatment outcome of patients with lung cancer and IPF was generally unfavorable, and acute exacerbation triggered by treatment frequently occurred.

PMID:33859288 | DOI:10.1038/s41598-021-87747-1

Thorax. 2021 Apr 15:thoraxjnl-2020-215962. doi: 10.1136/thoraxjnl-2020-215962. Online ahead of print.

ABSTRACT

RATIONALE: Extracellular vesicles (EVs) are small lipid vesicles, and EV-coupled microRNAs (miRNAs) are important modulators of biological processes. Fibrocytes are circulating bone marrow-derived cells that migrate into the injured lungs and contribute to fibrogenesis. The question of whether EV-coupled miRNAs derived from fibrocytes are able to regulate pulmonary fibrosis has not been addressed yet.

METHODS: Pulmonary fibrosis was induced in rats by intratracheal administration of an adenoviral gene vector encoding active transforming growth factor-β1 (TGF-β1) or control vector. Primary fibrocytes and fibroblasts were cultured from rat lungs and were sorted by anti-CD45 magnetic beads. Human circulating fibrocytes and fibrocytes in bronchoalveolar lavage fluid (BALF) were isolated by fibronectin-coated dishes. Fibrocytes were cultured on different stiffness plates or decellularised lung scaffolds. We also determined the effects of extracellular matrix (ECM) and recombinant TGF-β1 on the cellular and EV-coupled miRNA expression of fibrocytes.

RESULTS: The EVs of fibrocytes derived from fibrotic lungs significantly upregulated the expression of col1a1 of fibroblasts. Culturing on rigid plates or fibrotic decellularised lung scaffolds increased miR-21-5 p expression compared with soft plates or normal lung scaffolds. Dissolved ECM collected from fibrotic lungs and recombinant TGF-β1 increased miR-21-5 p expression on fibrocytes, and these effects were attenuated on soft plates. Fibrocytes from BALF collected from fibrotic interstitial pneumonia patients showed higher miR-21-5 p expression than those from other patients.

CONCLUSIONS: Our results indicate that ECM contributes to fibrogenesis through biomechanical and biochemical effects on miRNA expression in fibrocytes.

PMID:33859055 | DOI:10.1136/thoraxjnl-2020-215962

BMC Pulm Med. 2021 Apr 15;21(1):122. doi: 10.1186/s12890-021-01489-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with unclear pathogenesis. IPF is considered as a risk factor for lung cancer. Compared to other lung cancers, small-cell lung cancer (SCLC) has a lower incidence, but has a more aggressive course. Patients with IPF and SCLC have a lower survival rate, more difficult treatment, and poorer prognosis.

CASE PRESENTATION: Case 1 was of a 66-year-old man with IPF for 5 years, who was admitted to our hospital for dyspnea. Case 2 was of a 68-year-old woman, who presented with chest pains, cough, and dyspnea. Both patients had extremely poor lung function. High-resolution computed tomography and pathology revealed that both patients had IPF and SCLC. Chemotherapy comprising nedaplatin (80 mg/m2) and etoposide (100 mg for 5 days) was initiated for both patients. Antifibrotic agents were continued during the chemotherapeutic regimen. Both patients showed improvement in their condition after treatment.

CONCLUSION: The favorable outcomes in these 2 cases suggests that chemotherapy is worth considering in the management of patients having SCLC and IPF with poor lung function.

PMID:33858421 | DOI:10.1186/s12890-021-01489-4