Therapeutic induction of Bcl2‐associated athanogene 3‐mediated autophagy in idiopathic pulmonary fibrosis

Chillappagari, Shashi; Schwarz, Julian; Kesireddy, Vidyasagar; Knoell, Jessica; Korfei, Martina; Höetzenecker, Konrad; Behl, Christian; Bellusci, Saverio; Güenther, Andreas; Mahavadi, Poornima

doi:10.1002/ctm2.935

Cited by 8 publications

(6 citation statements)

References 58 publications

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“…Usual interstitial pneumonia (UIP) was the main pathological finding on all explant tissue ( Table 2 ). The models and assays performed in each PCLS culture are also summarized in Table 2 (22).…”

Section: Methodsmentioning

confidence: 99%

“…Collagen 1 alpha 1 (COL1A1) immunostaining was performed on tissue sections generated from 4 PCLS biological samples. Immunofluorescence using a COL1A1 (Rockland) monoclonal antibody was performed as described (22). Leica M205 FA Fluorescent Stereoscope (Leica Microsystems) and LAS-X-Core Software (3.7.4. version, LAS X Life Science, Leica Microsystems) was used for imaging.…”

Section: Methodsmentioning

confidence: 99%

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Pre-clinical proof-of-concept of anti-fibrotic activity of caveolin-1 scaffolding domain peptide LTI-03 inex vivoprecision cut lung slices from patients with Idiopathic Pulmonary Fibrosis

MacKenzie,

Mahavadi,

Jannini-Sa

et al. 2024

Preprint

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Rationale: While rodent lung fibrosis models are routinely used to evaluate novel antifibrotics, these models have largely failed to predict clinical efficacy of novel drug candidates for Idiopathic Pulmonary Fibrosis (IPF). Moreover, single target therapeutic strategies for IPF have failed and current multi-target standard of care drugs are not curative. Caveolin-1 (CAV-1) is an integral membrane protein, which, via its caveolin scaffolding domain (CSD), interacts with caveolin binding domains (CBD). CAV-1 regulates homeostasis, and its expression is decreased in IPF lungs. LTI-03 is a seven amino acid peptide derived from the CSD and formulated for dry powder inhalation; it was well tolerated in normal volunteers (NCT04233814) and a safety trial is underway in IPF patients (NCT05954988). Objectives: Anti-fibrotic efficacy of LTI-03 and other CSD peptides has been observed in IPF lung monocultures, and rodent pulmonary, dermal, and heart fibrosis models. This study aimed to characterize progressive fibrotic activity in IPF PCLS explants and to evaluate the antifibrotic effects of LTI-03 and nintedanib in this model. Methods: First, CBD regions were identified in IPF signaling proteins using in silico analysis. Then, IPF PCLS (n=8) were characterized by COL1A1 immunostaining, multiplex immunoassays, and bulk RNA sequencing following treatment every 12hrs with LTI-03 at 0.5, 3.0, or 10 μM; nintedanib at 0.1 μM or 1 μM; or control peptide (CP) at 10 μM. Measurements and Main Results: CBDs were present in proteins implicated in IPF, including VEGFR, FGFR and PDGFR. Increased expression of profibrotic mediators indicated active fibrotic activity in IPF PCLS over five days. LTI-03 dose dependently decreased COL1A1 staining, and like nintedanib, decreased profibrotic proteins and transcripts. Unlike nintedanib, LTI-03 did not induce cellular necrosis signals. Conclusion: IPF PCLS explants demonstrate molecular activity indicative of fibrosis during 5 days in culture and LTI-03 broadly attenuated pro-fibrotic proteins and pathways, further supporting the potential therapeutic effectiveness of LTI-03 for IPF.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Pre-clinical proof-of-concept of anti-fibrotic activity of caveolin-1 scaffolding domain peptide LTI-03 inex vivoprecision cut lung slices from patients with Idiopathic Pulmonary Fibrosis

MacKenzie,

Mahavadi,

Jannini-Sa

et al. 2024

Preprint

Self Cite

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“…However, lung transplants continue to face significant clinical constraints, primarily due to the shortage of available donors [ 114 ]. In addition to investigating autophagy mechanisms in IPF, multiple drugs have been introduced to mitigate the progression of the disease [ 115 ]. Furthermore, an array of compounds with therapeutic potential in IPF by modulating autophagy are steadily emerging [ 116 , 117 ].…”

Section: Targeting Autophagy In Ipfmentioning

confidence: 99%

Different Levels of Autophagy Activity in Mesenchymal Stem Cells Are Involved in the Progression of Idiopathic Pulmonary Fibrosis

Tao,

Lv,

Zhang

et al. 2024

Stem Cells International

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Idiopathic pulmonary fibrosis (IPF) is an age-related lung interstitial disease that occurs predominantly in people over 65 years of age and for which there is a lack of effective therapeutic agents. It has demonstrated that mesenchymal stem cells (MSCs) including alveolar epithelial cells (AECs) can perform repair functions. However, MSCs lose their repair functions due to their distinctive aging characteristics, eventually leading to the progression of IPF. Recent breakthroughs have revealed that the degree of autophagic activity influences the renewal and aging of MSCs and determines the prognosis of IPF. Autophagy is a lysosome-dependent pathway that mediates the degradation and recycling of intracellular material and is an efficient way to renew the nonnuclear (cytoplasmic) part of eukaryotic cells, which is essential for maintaining cellular homeostasis and is a potential target for regulating MSCs function. Therefore, this review focuses on the changes in autophagic activity of MSCs, clarifies the relationship between autophagy and health status of MSCs and the effect of autophagic activity on MSCs senescence and IPF, providing a theoretical basis for promoting the clinical application of MSCs.

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“…Studies in PCLS have supported a number of different molecules in the pathogenesis of IPF including: a transmembrane protein that can interact with growth factor receptors or extracellular ligands to modulate receptor activation [104]; activation of histone deacetylases [105]; activation of integrins [106]; ion channel activation [107]; a kinase and a signaling microdomain protein [108]; a protein involved in cell fate determination, motility, and organogenesis [109]; and even an miRNA mimic as a potential therapy [110]. Additionally, other pathways have been postulated to be part of specific aspects of the biology of both epithelial cells and fibroblasts that may play a role in the pathology of IPF [111][112][113][114][115][116][117][118][119][120][121]. Studies have utilized PCLS to identify the cell types that drive fibrosis signals and showed the ways in which PCLS can model IPF [122][123][124][125].…”

Section: Studies In Fibrotic Lung Diseasesmentioning

confidence: 99%

Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery

Koziol-White,

Gebski,

Cao

et al. 2024

Respir Res

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Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including fibrosis, injury, repair, and host defense mechanisms. This innovative methodology presents a unique opportunity to bridge the gap between traditional in vitro cell cultures and in vivo animal models, offering researchers a more accurate representation of the intricate microenvironment of the lung. PCLS require the precise sectioning of lung tissue to maintain its structural and functional integrity. These thin slices serve as invaluable tools for various research endeavors, particularly in the realm of airway diseases. By providing a controlled microenvironment, precision-cut lung slices empower researchers to dissect and comprehend the multifaceted interactions and responses within lung tissue, thereby advancing our understanding of pulmonary pathophysiology.

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Therapeutic induction of Bcl2‐associated athanogene 3‐mediated autophagy in idiopathic pulmonary fibrosis

Cited by 8 publications

References 58 publications

Pre-clinical proof-of-concept of anti-fibrotic activity of caveolin-1 scaffolding domain peptide LTI-03 inex vivoprecision cut lung slices from patients with Idiopathic Pulmonary Fibrosis

Pre-clinical proof-of-concept of anti-fibrotic activity of caveolin-1 scaffolding domain peptide LTI-03 inex vivoprecision cut lung slices from patients with Idiopathic Pulmonary Fibrosis

Different Levels of Autophagy Activity in Mesenchymal Stem Cells Are Involved in the Progression of Idiopathic Pulmonary Fibrosis

Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery

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