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Cell Reports. Medicine Mar 2023Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs)...
Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) regulate many biological processes; however, the functional contributions of IGFBP2 in lung fibrosis remain largely unclear. Here, we report that intranasal delivery of recombinant IGFBP2 protects aged mice from weight loss and demonstrated antifibrotic effects after bleomycin lung injury. Notably, aged human-Igfbp2 transgenic mice reveal reduced senescence and senescent-associated secretory phenotype factors in alveolar epithelial type 2 (AEC2) cells and they ameliorated bleomycin-induced lung fibrosis. Finally, we demonstrate that IGFBP2 expression is significantly suppressed in AEC2 cells isolated from fibrotic lung regions of patients with IPF and/or pulmonary hypertension compared with patients with hypersensitivity pneumonitis and/or chronic obstructive pulmonary disease. Altogether, our study provides insights into how IGFBP2 regulates AEC2-cell-specific senescence and that restoring IGFBP2 levels in fibrotic lungs can prove effective for patients with IPF.
Topics: Aged; Animals; Humans; Mice; Alveolar Epithelial Cells; Bleomycin; Cellular Senescence; Idiopathic Pulmonary Fibrosis; Mice, Transgenic
PubMed: 36787736
DOI: 10.1016/j.xcrm.2023.100945 -
Nature Communications Nov 2022Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays...
Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1 fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate.
Topics: Mice; Animals; Pulmonary Fibrosis; Mice, Inbred C57BL; Fibroblasts; Extracellular Matrix; Bleomycin
PubMed: 36402779
DOI: 10.1038/s41467-022-34870-w -
The Journal of Clinical Investigation May 2019Idiopathic Pulmonary Fibrosis (IPF) is a deadly disease with limited therapies. Tissue fibrosis is associated with Type 2 immune response, although the causal...
Idiopathic Pulmonary Fibrosis (IPF) is a deadly disease with limited therapies. Tissue fibrosis is associated with Type 2 immune response, although the causal contribution of immune cells is not defined. The AP-1 transcription factor Fra-2 is upregulated in IPF lung sections and Fra-2 transgenic mice (Fra-2tg) exhibit spontaneous lung fibrosis. Here we show that Bleomycin-induced lung fibrosis is attenuated upon myeloid-inactivation of Fra-2 and aggravated in Fra-2tg bone marrow chimeras. Type VI collagen (ColVI), a Fra-2 transcriptional target, is up-regulated in three lung fibrosis models, and macrophages promote myofibroblast activation in vitro in a ColVI- and Fra-2-dependent manner. Fra-2 or ColVI inactivation does not affect macrophage recruitment and alternative activation, suggesting that Fra-2/ColVI specifically controls the paracrine pro-fibrotic activity of macrophages. Importantly, ColVI knock-out mice (KO) and ColVI-KO bone marrow chimeras are protected from Bleomycin-induced lung fibrosis. Therapeutic administration of a Fra-2/AP-1 inhibitor reduces ColVI expression and ameliorates fibrosis in Fra-2tg mice and in the Bleomycin model. Finally, Fra-2 and ColVI positively correlate in IPF patient samples and co-localize in lung macrophages. Therefore, the Fra-2/ColVI pro-fibrotic axis is a promising biomarker and therapeutic target for lung fibrosis, and possibly other fibrotic diseases.
Topics: Allografts; Animals; Bleomycin; Bone Marrow; Bone Marrow Transplantation; Collagen Type VI; Fos-Related Antigen-2; Humans; Idiopathic Pulmonary Fibrosis; Macrophages; Mice; Mice, Knockout; Myofibroblasts; Transplantation Chimera
PubMed: 31135379
DOI: 10.1172/JCI125366 -
The New England Journal of Medicine Jun 2016We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma.
METHODS
Patients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PET-CT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points.
RESULTS
A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%.
CONCLUSIONS
Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy. (Funded by Cancer Research UK and Others; ClinicalTrials.gov number, NCT00678327.).
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Disease-Free Survival; Doxorubicin; Female; Hodgkin Disease; Humans; Male; Middle Aged; Positron-Emission Tomography; Prospective Studies; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome; Vinblastine; Young Adult
PubMed: 27332902
DOI: 10.1056/NEJMoa1510093 -
Biomedicine & Pharmacotherapy =... Sep 2022Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies...
BACKGROUND
Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies have found that IGU has certain advantages in improving lung function and shows great potential for pulmonary fibrosis therapy. However, the specific mechanism is not clear. This study was designed to observe and investigate the therapeutic effects of IGU on bleomycin-induced pulmonary fibrosis and further investigate its underlying mechanism.
METHODS
A mouse model of pulmonary fibrosis was induced by intratracheal injection of bleomycin (BLM). Model mice were randomly assigned to receive different concentrations of IGU. A TGF-β (T)-induced A549 epithelial-mesenchymal transition (EMT) cell model was utilized to investigate the effects of IGU on EMT in vitro. The NLRP3 inflammasome was activated by the costimulation of LPS+ATP (LA) to evaluate the effects of IGU in vitro.
RESULTS
We found that IGU resulted in favourable therapeutic outcomes by affecting inflammatory infiltration and collagen deposition. Additionally, the markers of the BLM-mediated EMT phenotype and NLRP3-activated phenotype in the lung were also attenuated after IGU administration. In vitro experiments, the results confirmed its anti-EMT and anti-NLRP3 inflammasome activation effects.We then found that the anti-lung fibrosis effect of IGU was accompanied by a decrease in reactive oxygen species (ROS) production.
CONCLUSION
IGU can inhibit the EMT process and NLRP3 inflammasome activation and reduce ROS production to ameliorate pulmonary fibrosis, which may provide new insights into the further application of IGU in interstitial pulmonary fibrosis.
Topics: Animals; Bleomycin; Chromones; Epithelial-Mesenchymal Transition; Inflammasomes; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Fibrosis; Reactive Oxygen Species; Sulfonamides
PubMed: 36076570
DOI: 10.1016/j.biopha.2022.113460 -
The European Respiratory Journal Jun 2020Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix accumulation in the lungs....
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterised by myofibroblast proliferation and abnormal extracellular matrix accumulation in the lungs. Transforming growth factor (TGF)-β1 initiates key profibrotic signalling involving the SMAD pathway and the small heat shock protein B5 (HSPB5). Tripartite motif-containing 33 (TRIM33) has been reported to negatively regulate TGF-β/SMAD signalling, but its role in fibrogenesis remains unknown. The objective of this study was to elucidate the role of TRIM33 in IPF.
METHODS
TRIM33 expression was assessed in the lungs of IPF patients and rodent fibrosis models. Bone marrow-derived macrophages (BMDM), primary lung fibroblasts and 3D lung tissue slices were isolated from -floxed mice and cultured with TGF-β1 or bleomycin (BLM). expression was then suppressed by adenovirus Cre recombinase (AdCre). Pulmonary fibrosis was evaluated in haematopoietic-specific knockout mice and in -floxed mice that received AdCre and BLM intratracheally.
RESULTS
TRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients and rodent fibrotic lungs. inhibition in BMDM increased TGF-β1 secretion upon BLM treatment. Haematopoietic-specific knockout sensitised mice to BLM-induced fibrosis. In primary lung fibroblasts and 3D lung tissue slices, deficiency increased expression of genes downstream of TGF-β1. In mice, AdCre- inhibition worsened BLM-induced fibrosis. , HSPB5 was able to bind directly to TRIM33, thereby diminishing its protein level and TRIM33/SMAD4 interaction.
CONCLUSION
Our results demonstrate a key role of TRIM33 as a negative regulator of lung fibrosis. Since TRIM33 directly associates with HSPB5, which impairs its activity, inhibitors of TRIM33/HSPB5 interaction may be of interest in the treatment of IPF.
Topics: Animals; Bleomycin; Disease Models, Animal; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Lung; Mice; Mice, Inbred C57BL; Signal Transduction; Transcription Factors; Transforming Growth Factor beta1
PubMed: 32184320
DOI: 10.1183/13993003.01346-2019 -
The European Respiratory Journal Nov 2022Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary...
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease associated with chronic inflammation and tissue remodelling leading to fibrosis, reduced pulmonary function, respiratory failure and death. Bleomycin (Blm)-induced lung fibrosis in mice replicates several clinical features of human IPF, including prominent lymphoid aggregates of predominantly B-cells that accumulate in the lung adjacent to areas of active fibrosis. We have shown previously a requirement for B-cells in the development of Blm-induced lung fibrosis in mice. To determine the therapeutic potential of inhibiting B-cell function in pulmonary fibrosis, we examined the effects of anti-CD20 B-cell ablation therapy to selectively remove mature B-cells from the immune system and inhibit Blm-induced lung fibrosis. Anti-CD20 B-cell ablation did not reduce fibrosis in this model; however, immune phenotyping of peripheral blood and lung resident cells revealed that anti-CD20-treated mice retained a high frequency of CD19 CD138 plasma cells. Interestingly, high levels of CD138 cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes plasma cells, reduced the level of Blm-induced lung fibrosis, implicating plasma cells as important effector cells in the development and progression of pulmonary fibrosis.
Topics: Humans; Mice; Animals; Bleomycin; Plasma Cells; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial
PubMed: 35798357
DOI: 10.1183/13993003.01469-2021 -
ELife May 2023Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that...
Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating 'indeterminate' states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after -induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz, and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both and (encoding Taz) or alone in AT2 cell stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, the inactivation of only in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz-mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.
Topics: Humans; Hippo Signaling Pathway; Lung; Adaptor Proteins, Signal Transducing; Idiopathic Pulmonary Fibrosis; Transcription Factors; Intracellular Signaling Peptides and Proteins; Bleomycin
PubMed: 37166104
DOI: 10.7554/eLife.85092 -
American Journal of Respiratory Cell... Aug 2022We previously identified a novel molecular subtype of idiopathic pulmonary fibrosis (IPF) defined by increased expression of cilium-associated genes, airway mucin gene ,...
We previously identified a novel molecular subtype of idiopathic pulmonary fibrosis (IPF) defined by increased expression of cilium-associated genes, airway mucin gene , and marker of basal cell airway progenitors. Here we show the association of and cilia gene expression in human IPF airway epithelial cells, providing further rationale for examining the role of cilium genes in the pathogenesis of IPF. We demonstrate increased multiciliogenesis and changes in motile cilia structure of multiciliated cells both in IPF and bleomycin lung fibrosis models. Importantly, conditional deletion of a cilium gene, Ift88 (intraflagellar transport 88), in Krt5 basal cells reduces Krt5 pod formation and lung fibrosis, whereas no changes are observed in Ift88 conditional deletion in club cell progenitors. Our findings indicate that aberrant injury-activated primary ciliogenesis and Hedgehog signaling may play a causative role in Krt5 pod formation, which leads to aberrant multiciliogenesis and lung fibrosis. This implies that modulating cilium gene expression in Krt5 cell progenitors is a potential therapeutic target for IPF.
Topics: Bleomycin; Cilia; Hedgehog Proteins; Humans; Idiopathic Pulmonary Fibrosis; Signal Transduction
PubMed: 35608953
DOI: 10.1165/rcmb.2021-0554OC -
Angiogenesis Nov 2021The loss of normal alveolar capillary and deregulated angiogenesis occurs simultaneously in idiopathic pulmonary fibrosis (IPF); however the contributions of specific...
The loss of normal alveolar capillary and deregulated angiogenesis occurs simultaneously in idiopathic pulmonary fibrosis (IPF); however the contributions of specific endothelial subpopulations in the development of pulmonary fibrosis are poorly understood. Herein, we perform single-cell RNA sequencing to characterize the heterogeneity of endothelial cells (ECs) in bleomycin (BLM)-induced lung fibrosis in rats. One subpopulation, characterized by the expression of Nos3 and Cav1, is mostly distributed in non-fibrotic lungs and also highly expresses genes related to the "response to mechanical stimulus" and "lung/heart morphogenesis" processes. Another subpopulation of ECs expanded in BLM-treated lungs, characterized by Cxcl12, is observed to be closely related to the pro-fibrotic process in the transcriptome data, such as "regulation of angiogenesis," "collagen binding," and "chemokine activity," and spatially localized to BLM-induced neovascularization. Using CellPhoneDB software, we generated a complex cell-cell interaction network, which predicts the potential roles of EC subpopulations in recruiting monocytes, inducing the proliferation of fibroblasts and promoting the production and remolding of the extracellular matrix (ECM). Taken together, our data demonstrate the high degree of heterogeneity of ECs in fibrotic lung and it is proposed that the interaction between ECs, macrophages, and stromal cells contributes to pathologic IPF.
Topics: Animals; Bleomycin; Endothelial Cells; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Mice; Mice, Inbred C57BL; Rats; Sequence Analysis, RNA
PubMed: 34028626
DOI: 10.1007/s10456-021-09795-5