Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatment modalities effective in slowing disease progression but not effective in restoring organ function or reversing fibrotic changes. When physiological wound repair is complete, myofibroblasts are programmed to undergo cell death and self-clearance, however, in fibrosis there is a characteristic absence of myofibroblast apoptosis. It has been shown that in fibrosis, myofibroblasts adopt an apoptotic-resistant, highly proliferative phenotype leading to persistent myofibroblast activation and perpetuation of the fibrotic disease process. Recently, this pathological adaptation has been linked to dysregulated expression of tumour suppressor gene p53. In this review, we discuss p53 dysregulation and apoptotic failure in myofibroblasts and demonstrate its consistent link to fibrotic disease development in all types of organ fibrosis. An enhanced understanding of the role of p53 dysregulation and myofibroblast apoptosis may aid in future novel therapeutic and/or diagnostic strategies in organ fibrosis.

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Summary A 53-year-old female presented to a tertiary ophthalmology referral centre complaining of unilateral painless loss of vision. Subsequent assessment revealed malignant hypertension causing right-sided cystoid macular oedema. During the course of secondary hypertension workup, she was diagnosed with a 7.8 cm phaeochromocytoma which was resected. Testing for a panel of all predisposing phaeochromocytoma-causing variants using next-generation sequencing resulted in the diagnosis of a novel SDHD variant. Learning points Screening for secondary causes of hypertension is indicated when there is evidence of hypertension-mediated end-organ damage (1). Testing for a predisposing variant should be considered in all patients with phaeochromocytoma or paraganglioma due to the high heritability rate and prevalence of somatic variants (2, 3, 4). Novel variants are commonly uncovered in the Succinate Dehydrogenase (SDH) subunit; proving pathogenicity is a complex, time-consuming process and one challenge of next-generation sequencing (3). SDHB immunohistochemistry as a tool for demonstrating pathogenicity is associated with reduced sensitivity when assessing SDHD variants (5, 6).

PurposePrimary open‐angle glaucoma (POAG) is an age‐related fibrotic condition and a leading cause of blindness worldwide. POAG‐related damage is initiated within the lamina cribrosa (LC) region of the optic nerve head, driven by the pathological activation of resident LC cells. LC cells bear striking similarities to proliferative, apoptotic‐resistant myofibroblasts known to be responsible for organ fibrosis. Myofibroblast dysregulation is linked to targeted proteasomal degradation of p53 by the E3 ubiquitin‐protein ligase MDM2 (mouse‐double‐minute‐2) thus negating p53’s important regulatory role in cell‐cycle/apoptosis. This project aims to evaluate the role of p53, MDM2, and the ubiquitin‐proteasomal pathway in glaucomatous LC cells.MethodsPrimary human normal LC (NLC) and glaucoma LC (GLC) cells (n = 3 donors) were cultured under standard conditions and treated for 48 hours with RG‐7112 (p53‐MDM2 interaction inhibitor, Abcam). The p53‐MDM2 ubiquitin‐proteasomal pathway was analysed by real‐time polymerase chain reaction (qRT‐PCR) for gene expression and protein levels via western blotting.ResultsMDM2 gene expression levels were significantly elevated (p = 0.006) in GLC cells (1.00 ± 0.12) versus NLC cells (0.89 ± 0.08). p53‐MDM2 inhibitor RG‐7112 treatment caused a further significant (p = 0.001) increase in MDM2 transcription levels in GLC cells (1.17 ± 0.04). p53 transcription levels were equivocal between GLC cells (0.88 ± 0.09) and NLC cells (0.87 ± 0.08), with RG‐7112 treatment leading to a significant increase (p = 0.028) in p53 transcription levels in GLC cells (0.95 ± 0.06). Western blot analysis showed significant decreased protein expression levels of p53 (0.76 ± 0.09)(p = 0.047) and increased protein expression of MDM2 (1.57 ± 0.33)(p = 0.042) in GLC cells compared to NLC. Interestingly, p53‐MDM2 inhibitor RG‐7112 treatment increased p53 (1.14 ± 0.43)(p = 0.267) and decreased MDM2 protein expression levels (0.92 ± 0.25)(p = 0.06) in GLC cells.ConclusionsOur data suggest the ubiquitin‐proteasomal pathway is significantly dysregulated in GLC cells with MDM2 led p53 protein degradation negatively impacting its key role as “guardian of the genome”. Targeting the p53 ubiquitin‐proteasomal pathway in lamina cribrosa fibrosis may lead to future novel therapeutic interventions.

A 48-year-old gentleman presented to the ophthalmology department with progressive monocular vision loss, a relative afferent-pupillary defect, decreased color perception, headache, proptosis, and retro-orbital pain. This particular patient’s demographics and disease course did not suggest a “typical” retro-bulbar optic neuritis and highlights the importance of avoiding presumptive steroid treatment in such “atypical” cases. Further investigations revealed a compressive optic neuropathy secondary to an orbital tumor (B-cell non-Hodgkin’s lymphoma) and were subsequently treated by a multi-disciplinary approach. Early detection and commencement of treatment is a crucial determining factor in orbital lymphoma prognosis and is therefore an important differential diagnosis for an ophthalmologist to consider when evaluating patients with “atypical” optic neuropathies.