Fibroblast Growth Facor 19, a Downregulated Factor in Idiopathic Pulmonary Fibrosis, Inhibits Mice Lung Fibrosis

Background: Nintedanib slows disease progression in patients with Idiopathic Pulmonary Fibrosis (IPF) by reducing decline in Forced Vital Capacity (FVC). The effects of nintedanib on abnormalities on high-resolution computed tomography scans have not been previously studied. Objective: We conducted a Phase IIIb trial to assess the effects of nintedanib on changes in Quantitative Lung Fibrosis (QLF) score and other measures of disease progression in patients with IPF. Methods: 113 patients were randomized 1:1 to receive nintedanib 150 mg bid or placebo double-blind for ≥6 months, followed by open-label nintedanib. The primary endpoint was the relative change from baseline in QLF score (%) at month 6. Analyses were descriptive and exploratory. Results: Adjusted mean relative changes from baseline in QLF score at month 6 were 11.4% in the nintedanib group (n=42) and 14.6% in the placebo group (n=45) (difference 3.2% [95% CI: −9.2, 15.6]). Adjusted mean absolute changes from baseline in QLF score at month 6 were 0.98% and 1.33% in these groups, respectively (difference 0.35% [95% CI: −1.27, 1.96]). Adjusted mean absolute changes from baseline in FVC at month 6 were −14.2 mL and −83.2 mL in the nintedanib (n=54) and placebo (n=54) groups, respectively (difference 69.0 mL [95% CI: −8.7, 146.8]). Conclusion: Exploratory data suggest that in patients with IPF, 6 months’ treatment with nintedanib was associated with a numerically smaller degree of fibrotic change in the lungs and reduced FVC decline versus placebo. These data support previous findings that nintedanib slows the progression of IPF.

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Increased Procollagen III Aminoterminal Peptide-related Antigens and Fibroblast Growth Signals in the Lungs of Patients with Idiopathic Pulmonary Fibrosis

American Review of Respiratory Disease ◽

10.1164/ajrccm/137.3.572 ◽

1988 ◽

Vol 137 (3) ◽

pp. 572-578 ◽

Cited By ~ 48

Author(s):

André M. Cantin ◽

Robert Boileau ◽

Raymond Bégin

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Fibroblast Growth ◽

Procollagen Iii

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Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis

10.1101/2020.01.16.908749 ◽

2020 ◽

Author(s):

Emily Fraser ◽

Laura Denney ◽

Karl Blirando ◽

Chaitanya Vuppusetty ◽

Agne Antanaviciute ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Immune Cells ◽

Therapeutic Target ◽

Lung Fibrosis ◽

Ex Vivo ◽

Treatment Options ◽

Gene Expression Signature ◽

Severe Form

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytes ex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.

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Association of circulating cell-free double-stranded DNA and metabolic derangements in idiopathic pulmonary fibrosis

Thorax ◽

10.1136/thoraxjnl-2021-217315 ◽

2021 ◽

pp. thoraxjnl-2021-217315

Author(s):

William Whalen ◽

Mustafa Buyukozkan ◽

Bethany Moore ◽

Jong-Seok Moon ◽

Charles S Dela Cruz ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Rapid Progression ◽

Healthy Controls ◽

Double Stranded Dna ◽

Slow Progressors ◽

Progression Of Disease

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear aetiology and poorly understood pathophysiology. Although plasma levels of circulating cell-free DNA (ccf-DNA) and metabolomic changes have been reported in IPF, the associations between ccf-DNA levels and metabolic derangements in lung fibrosis are unclear. Here, we demonstrate that ccf-double-stranded DNA (dsDNA) is increased in patients with IPF with rapid progression of disease compared with slow progressors and healthy controls and that ccf-dsDNA associates with amino acid metabolism, energy metabolism and lipid metabolism pathways in patients with IPF.

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PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.676702 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrea Doni ◽

Alberto Mantovani ◽

Barbara Bottazzi ◽

Remo Castro Russo

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Tissue Repair ◽

Therapeutic Potential ◽

Tissue Injury ◽

Life Quality ◽

Unknown Origin ◽

Protective Role

PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient’s life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF.

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Itaconate controls the severity of pulmonary fibrosis

Science Immunology ◽

10.1126/sciimmunol.abc1884 ◽

2020 ◽

Vol 5 (52) ◽

pp. eabc1884 ◽

Cited By ~ 1

Author(s):

Patricia P. Ogger ◽

Gesa J. Albers ◽

Richard J. Hewitt ◽

Brendan J. O’Sullivan ◽

Joseph E. Powell ◽

...

Keyword(s):

Gene Expression ◽

Wound Healing ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Therapeutic Strategy ◽

Lung Fibroblasts ◽

Disease Phenotype ◽

Wild Type

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1−/− mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1−/− tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.

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Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2013-0342oc ◽

2014 ◽

Vol 50 (5) ◽

pp. 985-994 ◽

Cited By ~ 77

Author(s):

Lynne A. Murray ◽

Huilan Zhang ◽

Sameer R. Oak ◽

Ana Lucia Coelho ◽

Athula Herath ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Epithelial Damage ◽

Interleukin 13

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Coagulation and anticoagulation in idiopathic pulmonary fibrosis

European Respiratory Review ◽

10.1183/16000617.00008414 ◽

2015 ◽

Vol 24 (137) ◽

pp. 392-399 ◽

Cited By ~ 19

Author(s):

Michael G. Crooks ◽

Simon P. Hart

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Oral Anticoagulants ◽

Epidemiological Studies ◽

Prothrombotic State ◽

Vascular Events ◽

Thrombotic Risk ◽

Trial Outcomes ◽

Alveolar Compartment

Idiopathic pulmonary fibrosis (IPF) is an incurable, progressive interstitial lung disease with a prognosis that is worse than that of many cancers. Epidemiological studies have demonstrated a link between IPF and thrombotic vascular events. Coagulation and fibrinolytic systems play central roles in wound healing and repair, processes hypothesised to be abnormal within the IPF lung. Animal models of pulmonary fibrosis have demonstrated an imbalance between thrombosis and fibrinolysis within the alveolar compartment, a finding that is also observed in IPF patients. A systemic prothrombotic state also occurs in IPF and is associated with increased mortality, but trials of anticoagulation in IPF have provided conflicting results. Differences in methodology, intervention and study populations may contribute to the inconsistent trial outcomes. The new oral anticoagulants have properties that may prove advantageous in targeting both thrombotic risk and progression of lung fibrosis.

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