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BackgroundMyo-inositol (or inositol) and its derivatives not only function as important metabolites for multiple cellular processes but also act as co-factors and second messengers in signaling pathways. Although inositol supplementation has been widely studied in various clinical trials, little is known about its effect on idiopathic pulmonary fibrosis (IPF). Recent studies have demonstrated that IPF lung fibroblasts display arginine dependency due to loss of argininosuccinate synthase 1 (ASS1). However, the metabolic mechanisms underlying ASS1 deficiency and its functional consequence in fibrogenic processes are yet to be elucidated.MethodsMetabolites extracted from primary lung fibroblasts with different ASS1 status were subjected to untargeted metabolomics analysis. An association of ASS1 deficiency with inositol and its signaling in lung fibroblasts was assessed using molecular biology assays. The therapeutic potential of inositol supplementation in fibroblast phenotypes and lung fibrosis was evaluated in cell-based studies and a bleomycin animal model, respectively.ResultsOur metabolomics studies showed that ASS1-deficient lung fibroblasts derived from IPF patients had significantly altered inositol phosphate metabolism. We observed that decreased inositol-4-monophosphate abundance and increased inositol abundance were associated with ASS1 expression in fibroblasts. Furthermore, genetic knockdown of ASS1 expression in primary normal lung fibroblasts led to the activation of inositol-mediated signalosomes, including EGFR and PKC signaling. Treatment with inositol significantly downregulated ASS1 deficiency-mediated signaling pathways and reduced cell invasiveness in IPF lung fibroblasts. Notably, inositol supplementation also mitigated bleomycin-induced fibrotic lesions and collagen deposition in mice.ConclusionThese findings taken together demonstrate a novel function of inositol in fibrometabolism and pulmonary fibrosis. Our study provides new evidence f

Argininosuccinate synthase 1 (ASS1) serves as a critical enzyme in arginine biosynthesis; however, its role in interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), remains largely unknown. This study aims at characterization and targeting of ASS1 deficiency in pulmonary fibrosis. We find that ASS1 was significantly decreased and inversely correlated with fibrotic status. Transcriptional downregulation of ASS1 was noted in fibroblastic foci of primary lung fibroblasts isolated from IPF patients. Genetic manipulations of ASS1 studies confirm that ASS1 expression inhibited fibroblast cell proliferation, migration, and invasion. We further show that the hepatocyte growth factor receptor (Met) receptor was activated and acted upstream of the Src-STAT3 axis signaling in ASS1-knockdown fibroblasts. Interestingly, both arginine-free conditions and arginine deiminase treatment were demonstrated to kill fibrotic fibroblasts, attenuated bleomycin-induced pulmonary fibrosis in mice, as well as synergistically increased nintedanib efficacy. Our data suggest ASS1 deficiency as a druggable target and also provide a unique therapeutic strategy against pulmonary fibrosis.

PurposeWe sought to characterize juxtapapillary (JP) and non-JP microvasculature dropout in patients with primary open-angle glaucoma and to compare their rate of retinal nerve fiber layer (RNFL) thinning.DesignRetrospective cohort study.MethodsA total of 141 eyes with primary open-angle glaucoma with ≥4 serial optical coherence tomography (OCT) images after initial OCT angiography for ≥2 years were included. Based on OCT angiography imaging, the 3 groups were matched by age and visual field mean deviation: JP group (parapapillary deep-layer microvasculature dropout in contact with the optic disc boundary, n = 47), non-JP group (dropout not reaching the optic disc boundary, n = 47), and no-dropout group (lacking the dropout, n = 47). The RNFL thinning rate was compared among the 3 groups.ResultsThe rate of RNFL thinning tended to be fastest in the JP group followed by the non-JP group and no-dropout group in all areas except the temporal and nasal sectors. Post hoc analysis revealed that the JP group had significantly faster RNFL thinning than did the no-dropout group in the global area and the inferotemporal and inferonasal sectors (P < .05). When subgroup analysis was performed for subjects in which the main sector of dropout was the inferotemporal sector, the JP group had significantly faster RNFL thinning than the other 2 groups in the corresponding inferotemporal sector (P < .001).ConclusionEyes with JP microvasculature dropout showed faster RNFL thinning than eyes without dropout. These findings suggest that deep-layer microvasculature dropout, especially in contact with the optic disc boundary, is associated with rapid glaucoma progression.

PurposeWe sought to characterize juxtapapillary (JP) and non-JP microvasculature dropout in patients with primary open-angle glaucoma and to compare their rate of retinal nerve fiber layer (RNFL) thinning.DesignRetrospective cohort study.MethodsA total of 141 eyes with primary open-angle glaucoma with ≥4 serial optical coherence tomography (OCT) images after initial OCT angiography for ≥2 years were included. Based on OCT angiography imaging, the 3 groups were matched by age and visual field mean deviation: JP group (parapapillary deep-layer microvasculature dropout in contact with the optic disc boundary, n = 47), non-JP group (dropout not reaching the optic disc boundary, n = 47), and no-dropout group (lacking the dropout, n = 47). The RNFL thinning rate was compared among the 3 groups.ResultsThe rate of RNFL thinning tended to be fastest in the JP group followed by the non-JP group and no-dropout group in all areas except the temporal and nasal sectors. Post hoc analysis revealed that the JP group had significantly faster RNFL thinning than did the no-dropout group in the global area and the inferotemporal and inferonasal sectors (P < .05). When subgroup analysis was performed for subjects in which the main sector of dropout was the inferotemporal sector, the JP group had significantly faster RNFL thinning than the other 2 groups in the corresponding inferotemporal sector (P < .001).ConclusionEyes with JP microvasculature dropout showed faster RNFL thinning than eyes without dropout. These findings suggest that deep-layer microvasculature dropout, especially in contact with the optic disc boundary, is associated with rapid glaucoma progression.