Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis

Espíndola, Milena S.; Habiel, David M.; Narayanan, Rohan; Jones, Isabelle; Coelho, Ana Lúcia; Murray, Lynne A.; Jiang, Dianhua; Noble, Paul W.; Hogaboam, Cory M.

doi:10.1164/rccm.201707-1519oc

Cited by 77 publications

(75 citation statements)

References 30 publications

(34 reference statements)

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“…This humanized IPF model was first used to study the in vivo role of CC chemokine receptor 7 (CCR7) in IPF (29); this model allows for cell trafficking during different stages of fibrosis development and progression, and offers unique insights into different fibroblast populations (13). Since the establishment of this model, several more studies have used it to study the heterogeneity of IPF fibroblasts and to explore antifibrotic agents with human specificity (13,(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis

Geng¹,

Liu²,

Liang³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 99%

PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis

Geng¹,

Liu²,

Liang³

et al. 2019

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“…Growth Arrest Specific 6 (GAS6) was significantly upregulated in in IPF AEC2 (Figure 4c). GAS6 mediated macrophage inflammation (Shibata et al, 2014) and Gas6 was increased in IPF fibroblasts (Espindola et al, 2018). The role of IFN genes and GAS6 in AEC2s is unknown.…”

Section: Ipf Aec2s Showed Similar Gene Signatures Of Murine Aec2-2 Anmentioning

confidence: 98%

Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

Liang

Huang

Liu

et al. 2020

Preprint

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Aging is a critical risk factor in progressive lung fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Loss of integrity of type 2 alveolar epithelial cells (AEC2s) is the main causal event in the pathogenesis of IPF. To systematically examine the genomic program changes of AEC2s with aging and lung injury, we performed unbiased single cell RNA-seq analyses of lung epithelial cells from either uninjured or bleomycin-injured young and old mice. Major lung epithelial cell types were readily identified with canonical cell markers in our dataset. Heterogenecity of AEC2s was apparent, and AEC2s were then classified into three subsets according to their gene signatures. Genes related to lipid metabolism and glycolysis were significantly altered within these three clusters of AEC2s, and also affected by aging and lung injury. Importantly, IPF AEC2s showed similar genomic programming and metabolic changes as that of AEC2s from bleomycin injured old mouse lungs relative to controls. Furthermore, perturbation of both lipid metabolism and glycolysis significantly changed progenitor renewal capacity in 3-Demensional organoid culture of AEC2s. Taken togather, this work identified metabolic defects of AEC2s in aging and during lung injury. Strategies to rectify these altered programs would promote AEC2 renewal which in turn improves lung repair.One sentence summaryMetabolic defects of alveolar progenitors in aging and during lung injury impair their renewal.

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“…In our study using a humanized SCID mouse model to examine pulmonary fibrosis, we did not observe either a preventative or therapeutic effect of Simtuzumab. The introduction of primary lung cells from IPF explants initiates and sustains a fibrotic response in the lungs of humanized SCID mice and we have observed that this model is responsive to anti-fibrotic therapies 19 , although Nintedanib showed no therapeutic effect in the humanized SCID IPF fibroblast model 21 . The failure of Simtuzumab in this model was unlike that observed in the bleomycin-induced pulmonary fibrosis model 16 , and highlights the need for multiple model testing before moving a target into the clinic.…”

Section: Discussionmentioning

confidence: 90%

“…IPF surgical lung biopsy samples were obtained as previously described 20 . IPF lung fibroblasts were generated by mechanically dissociating IPF lung biopsies or explants as previously described 21 .…”

Section: Isolation and Culture Of Primary Pulmonary Fibroblast Linesmentioning

confidence: 99%

Targeting Lysyl oxidase-like 2 in Idiopathic Pulmonary Fibrosis

Espíndola

Habiel

Coelho

et al. 2019

Preprint

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The composition of extracellular matrix (ECM) is altered during pathologic scarring in damaged organs including the lung. One major change in the ECM involves the crosslinking of collagen, which promotes fibroblast to myofibroblast differentiation. Objective:We examined the role of lysyl oxidase (LOX)-like 2 in lung fibroblasts cultured from normal or IPF lung samples and in a humanized mouse model of IPF using a monoclonal antibody (Simtuzumab). Research Design and Methods: Primary lung fibroblasts from normal donor lungs and IPF lung explants were examined for expression of LOXL2. Targeting LOXL2 with Simtuzumab on normal and IPF fibroblasts was examined both in vitro and in vivo for synthetic, functional, and profibrotic properties. Results: LOXL2 was increased at transcript and protein level in IPF compared with normal lung samples. In a dose-dependent manner, Simtuzumab enhanced differentiation of fibroblasts into myofibroblasts. Inhibition of LOXL2 also enhanced fibroblast invasion and accelerated the outgrowth of fibroblasts from dissociated human lung cell preparations. Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis. Conclusion: Consistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays.

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Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis

Abstract: Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.

Cited by 77 publications

References 30 publications

PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis

PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis

Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

Targeting Lysyl oxidase-like 2 in Idiopathic Pulmonary Fibrosis

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