Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarisation through phosphorylation of STAT3

Li, Qingfang; Cheng, Yuan; Zhang, Zhe; Bi, Zhenfei; Ma, Xuelei; Wei, Yuquan; Wei, Xiawei

doi:10.1002/ctm2.1036

Cited by 31 publications

(16 citation statements)

References 90 publications

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“…In the present study, the influence of the G6PD mutation was assessed by performing immunoblotting. Western blotting was performed as previously described ( Dong et al, 2019 ; Li et al, 2022 ; Wang et al, 2022 ). Cytoplasmic and nuclear protein extraction was performed using NE-PER™ Nuclear and Cytoplasmic Extraction Reagents (Thermo Fisher Scientific, United States).…”

Section: Methodsmentioning

confidence: 99%

Severe G6PD deficiency leads to recurrent infections and defects in ROS production: Case report and literature review

Sun

Dong

et al. 2022

Front. Genet.

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Purpose: Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency can lead to reduced nicotinamide adenine dinucleotide phosphate oxidase activity in phagocytes, resulting in immunodeficiency, with a limited number of reported cases. Here, we aimed to report a child with severe G6PD deficiency in China and investigate the mechanism of his recurrent infections.Methods: The clinical manifestations and immunological phenotypes of this patient were retrospectively collected. Gene mutation was detected by whole-exome sequencing and confirmed by Sanger sequencing. Dihydrorhodamine (DHR) analysis was performed to measure the respiratory burst of neutrophils. Messenger ribonucleic acid and protein levels were detected in the patient under lipopolysaccharide stimulation by real-time quantitative reverse transcription polymerase chain reaction and Western blot. A review of the literature was performed.Results: A male child with G6PD deficiency presented with recurrent respiratory infections, Epstein‒Barr virus infection and tonsillitis from 8 months of age. Gene testing revealed that the proband had one hemizygous mutation in the G6PD gene (c.496 C>T, p. R166C), inherited from his mother. This mutation might affect hydrophobic binding, and the G6PD enzyme activity of the patient was 0. The stimulation indexes of the neutrophils in the patient and mother were 22 and 37, respectively. Compared with healthy controls, decreased reactive oxygen species (ROS) production was observed in the patient. Activation of nuclear factor kappa-B (NF-κB) signaling was found to be influenced, and the synthesis of tumor necrosis factor alpha (TNF-α) was downregulated in the patient-derived cells. In neutrophils of his mother, 74.71% of the X chromosome carrying the mutated gene was inactivated. By performing a systematic literature review, an additional 15 patients with severe G6PD deficiency and recurrent infections were identified. Four other G6PD gene mutations have been reported, including c.1157T>A, c.180_182del, c.514C>T, and c.953_976del.Conclusion: Severe G6PD deficiency, not only class I but also class II, can contribute to a chronic granulomatous disease-like phenotype. Decreased reactive oxygen species synthesis led to decreased activation of the NF-κB pathway in G6PD-deficient patients. Children with severe G6PD deficiency should be aware of immunodeficiency disease, and the DHR assay is recommended to evaluate neutrophil function for early identification.

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Section: Methodsmentioning

confidence: 99%

Severe G6PD deficiency leads to recurrent infections and defects in ROS production: Case report and literature review

Sun

Dong

et al. 2022

Front. Genet.

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“…It has been demonstrated that treatment with intraperitoneal compound 7 (100 mg/kg) reduced the degree of PF and improved lung function in a mouse model of PF induced by BLM. These effects were observed in addition to a slight decrease in lung wet weight and lung index . In vitro, through the downregulation of profibrotic gene transcription, stress fiber production, myofibroblast activation, and collagen deposition, compound 7 reduced aberrant profibrotic signaling.…”

Section: Rock Inhibitorsmentioning

confidence: 99%

“…These effects were observed in addition to a slight decrease in lung wet weight and lung index. 46 In vitro, through the downregulation of profibrotic gene transcription, stress fiber production, myofibroblast activation, and collagen deposition, compound 7 reduced aberrant profibrotic signaling. Additionally, compound 7 reduced the level of connective tissue growth factor mRNA and remodeled the actin cytoskeleton in smooth muscle cells originating from human fibrosis.…”

Section: Rock Inhibitorsmentioning

confidence: 99%

“…Since its discovery, ROCK has become a research hotspot, and reports have indicated multiple functions of ROCK, including the regulation of cell contraction and polarity, adhesion, motility, proliferation, apoptosis, differentiation, maturation and ECM deposition, all of which may play roles in PF progression. 45,46…”

Section: Introductionmentioning

confidence: 99%

“…In summary, the biological consequences of ROCK inhibition depend on the cell type, the cellular environment, and the microenvironment in which it resides. Since its discovery, ROCK has become a research hotspot, and reports have indicated multiple functions of ROCK, including the regulation of cell contraction and polarity, adhesion, motility, proliferation, apoptosis, differentiation, maturation and ECM deposition, all of which may play roles in PF progression. , …”

Section: A Brief Introduction To Rockmentioning

confidence: 99%

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Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

et al. 2023

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Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure–activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.

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Persistence of lung structural and functional alterations at one year post‐COVID‐19 is associated with increased serum PD‐L2 levels and altered CD4/CD8 ratio

Buendia‐Roldan,

Martínez‐Espinosa,

Aguirre

et al. 2024

Immunity Inflam & Disease

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BackgroundPersistent respiratory symptoms and lung abnormalities post‐COVID‐19 are public health problems. This study evaluated biomarkers to stratify high‐risk patients to the development or persistence of post‐COVID‐19 interstitial lung disease.MethodsOne hundred eighteen patients discharged with residual lung abnormalities compatible with interstitial lung disease (COVID‐ILD patients) after a severe COVID‐19 were followed for 1 year (post‐COVID‐ILD patients). Physical examination, pulmonary function tests, and chest high‐resolution computed tomography (HRCT) were performed. Soluble forms (s) of PD‐L1, PD‐L2, TIM‐3, and GAL‐9 were evaluated in serum and cell culture supernatant, as well as T‐cells subsets and the transmembrane expression of PD‐L1 and PD‐L2 on the cell surface.ResultsEighty percent of the post‐COVID‐ILD patients normalized their lung function at 1‐year follow‐up, 8% presented COVID‐independent ILD, and 12% still showed functional and HRCT alterations. PD‐L2 levels were heterogeneous during acute COVID‐19 (aCOVID); patients who increased (at least 30%) their sPD‐L2 levels at 1 year post‐COVID‐19 and exhibited altered CD4/CD8 ratio showed persistence of chest tomographic and functional alterations. By contrast, patients who decreased sPD‐L2 displayed a complete lung recovery. sPD‐L1, sTIM‐3, and sGAL‐9 increased significantly during aCOVID and decreased in all patients after 1‐year follow‐up.ConclusionIncreased sPD‐L2 and an altered CD4/CD8 ratio after 12 months of aCOVID are associated with the persistence of lung lesions, suggesting that they may contribute to lung damage post‐COVID‐19.

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Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarisation through phosphorylation of STAT3

Cited by 31 publications

References 90 publications

Severe G6PD deficiency leads to recurrent infections and defects in ROS production: Case report and literature review

Severe G6PD deficiency leads to recurrent infections and defects in ROS production: Case report and literature review

Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

Persistence of lung structural and functional alterations at one year post‐COVID‐19 is associated with increased serum PD‐L2 levels and altered CD4/CD8 ratio

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