The Role of Immunity and Inflammation in IPF Pathogenesis

Butler, Marcus W.; Keane, Michael P.

doi:10.1007/978-3-319-99975-3_6

Cited by 11 publications

(17 citation statements)

References 160 publications

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“…Giemsa-Wright stains of BALF further elucidated the increase in inflammatory macrophage numbers in the bleomycin-treated samples compared to TH5487/bleomycin samples. Inflammatory cell incursion into the lung environment plays a role in IPF progression and severity (16, 43), with limitation of lung inflammation providing a potential source of IPF limitation.…”

Section: Discussionmentioning

confidence: 99%

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

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Bonghir

et al. 2021

Preprint

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Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues together with aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to treat underlying causes of disease. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, a novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF.

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Section: Discussionmentioning

confidence: 99%

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

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Single

Bonghir

et al. 2021

Preprint

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“…The relative conversion efficiency arises in part from the phase-mismatch,

, which is defined by

, where

and

are the wave vectors for the SHG and incident photons, respectively. Here the SHG intensity is modulated by a sinc 2 function of

, where a smaller phase-mismatch results in higher intensity. 19 In the current case, a higher local density of collagen molecules will arise upon enhanced crosslinking and will lead to increased SHG intensity over the Ctrl condition as the phase-mismatch will be lower (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…While IPF etiology is poorly understood, it has been attributed to a non-specific combination of both genetic and environmental factors, which promote repetitive alveolar injuries. 1 – 3 Upon injury, alveolar epithelial cells are aberrantly activated and secrete profibrotic cytokines, especially transforming growth factor-beta (TGF-

). 3 Fibroblast activation by TGF-

results in a highly contractile and myofibroblast phenotype, which serves as the primary effector cell for increased collagen (and other matrix proteins) production and extensive tissue remodeling.…”

Section: Introductionmentioning

confidence: 99%

Examining lysyl oxidase-like modulation of collagen architecture in 3D spheroid models of idiopathic pulmonary fibrosis via second-harmonic generation microscopy

et al. 2021

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. Significance: Idiopathic pulmonary fibrosis (IPF) patients have a poor prognosis with short lifespan following diagnosis as there are limited effective treatment options. Despite matrix stiffening being the hallmark of the disease there remains a lack of knowledge surrounding the underlying collagen alterations in the disease. Specifically, while increased collagen crosslinking has been implicated, the resulting effects on collagen macro/supramolecular changes have not been explored. Aim: We sought to determine if second-harmonic generation (SHG) microscopy could characterize differences in the collagen architecture in 3D spheroid models of IPF grown under different crosslinking modulation conditions (promotion and inhibition). Approach: We used SHG metrics based on the fiber morphology, relative SHG brightness, and macro/supramolecular structure by SHG polarization analyses to compare the structure of the IPF spheroids. Results: Comparison of the fiber morphology of the spheroids showed that the control group had the longest, straightest, and thickest fibers. The spheroids with crosslink enhancement and inhibition had the highest and lowest SHG conversion efficiencies, respectively, consistent with the resulting harmonophore density. SHG polarization analyses showed that the peptide pitch angle, alignment of collagen molecules, and overall chirality were altered upon crosslink modulation and were also consistent with reduced organization relative to the control group. Conclusions: While no single SHG signature is associated with crosslinking, we show that the suite of metrics used here is effective in delineating alterations across the collagen architecture sizescales. The results largely mirror those of human tissues and demonstrate that the combination of 3D spheroid models and SHG analysis is a powerful approach for hypothesis testing the roles of operative cellular and molecular factors in IPF.

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“…A study in 2004 shows that, in a mouse IPF model, decreased NK cell recruitment leads to reduced production of IFN-γ, which further enhances pulmonary fibrosis. 54 Although pre-clinical trials and small-scale clinical trials report therapeutic effects of exogenous IFN-γ in treating IPF, 55 – 60 double-blinded, multiple-centered clinical trials show that this IFN-γ treatment does not benefit IPF patients. 61 , 62 Recent studies, on the contrary, demonstrate a possible deteriorating effect on IPF of NK cell-mediated cytotoxicity and its principle product, IFN.…”

Section: Discussionmentioning

confidence: 99%

“… 1 – 3 Studies have shown that the innate immunity system, macrophages, chemotactic cytokines, and interleukins have pivotal impacts on the scarring and fibrosis progress in IPF. 4 – 6 As a component of the innate immunity, natural killer (NK) cells have been found depleted in lung tissue of IPF patients, 7 and the increased bronchial NK cell count is associated with impairment of IPF patients’ respiratory function. 8 The imbalanced immune response initiates endothelial apoptosis, 9 , 10 which further exacerbates the irreversible process of fibrosis under the interaction with cell migration and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Gene fusion of IL7 involved in the regulation of idiopathic pulmonary fibrosis

Sun

Huang

Leng

et al. 2021

Ther Adv Respir Dis

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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.

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The Role of Immunity and Inflammation in IPF Pathogenesis

Cited by 11 publications

References 160 publications

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Examining lysyl oxidase-like modulation of collagen architecture in 3D spheroid models of idiopathic pulmonary fibrosis via second-harmonic generation microscopy

Gene fusion of IL7 involved in the regulation of idiopathic pulmonary fibrosis

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