Strategies for anti-fibrotic therapies.

The fibrotic diseases encompass a wide spectrum of entities including such multisystemic diseases as systemic sclerosis, nephrogenic systemic fibrosis and sclerodermatous graft versus host disease, as well as organ-specific disorders such as pulmonary, liver, and kidney fibrosis. Collectively, given the wide variety of affected organs, the chronic nature of the fibrotic processes, and the large number of individuals suffering their devastating effects, these diseases pose one of the most serious health problems in current medicine and a serious economic burden to society. Despite these considerations there is currently no accepted effective treatment. However, remarkable progress has been achieved in the elucidation of their pathogenesis including the identification of the critical role of myofibroblasts and the determination of molecular mechanisms that result in the transcriptional activation of the genes responsible for the fibrotic process. Here we review the origin of the myofibroblast and discuss the crucial regulatory pathways involving multiple growth factors and cytokines that participate in the pathogenesis of the fibrotic process. Potentially effective therapeutic strategies based upon this new information are considered in detail and the major challenges that remain and their possible solutions are presented. It is expected that translational efforts devoted to convert this new knowledge into novel and effective anti-fibrotic drugs will be forthcoming in the near future. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease

Role of protein kinase C-delta in the regulation of collagen gene expression in scleroderma fibroblasts

Working with cultured dermal fibroblasts derived from control individuals and patients with systemic sclerosis (SSc), we have examined the effects of protein kinase C-delta (PKC-delta) on type I collagen biosynthesis and steady-state levels of COL1A1 and COL3A1 mRNAs. Rottlerin, a specific inhibitor of PKC-delta, exerted a powerful, dose-dependent inhibition of type I and type III collagen gene expression in normal and SSc cells. Optimal rottlerin concentrations caused a 70-90% inhibition of type I collagen production, a \u3e80% reduction in COL1A1 mRNA, and a \u3e70% reduction in COL3A1 mRNA in both cell types. In vitro nuclear transcription assays and transient transfections with COL1A1 promoter deletion constructs demonstrated that rottlerin profoundly reduced COL1A1 transcription and that this effect required a 129-bp promoter region encompassing nucleotides -804 to -675. This COL1A1 segment imparted rottlerin sensitivity to a heterologous promoter. Cotransfections of COL1A1 promoter constructs with a dominant-negative PKC-delta expression plasmid showed that suppression of this kinase silenced COL1A1 promoter activity. The results indicate that PKC-delta participates in the upregulation of collagen gene transcription in SSc and suggest that treatment with PKC-delta inhibitors could suppress fibrosis in this disease

Chronic pain, psychopathology, and DSM-5 somatic symptom disorder

Unlike acute pain that warns us of injury or disease, chronic or persistent pain serves no adaptive purpose. Though there is no agreed on definition of chronic pain, it is commonly referred to as pain that is without biological value, lasting longer than the typical healing time, not responsive to treatments based on specific remedies, and of a duration greater than 6 months. Chronic pain that is severe and intractable has detrimental consequences, including psychological distress, job loss, social isolation, and, not surprisingly, it is highly comorbid with depression and anxiety. Historically, pain without an apparent anatomical or neurophysiological origin was labelled as psychopathological. This approach is damaging to the patient and provider alike. It pollutes the therapeutic relationship by introducing an element of mutual distrust as well as implicit, if not explicit, blame. It is demoralizing to the patient who feels at fault, disbelieved, and alone. Moreover, many medically unexplained pains are now understood to involve an interplay between peripheral and central neurophysiological mechanisms that have gone awry. The new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, somatic symptom disorder overpsychologizes people with chronic pain; it has low sensitivity and specificity, and it contributes to misdiagnosis, as well as unnecessary stigma. Adjustment disorder remains the most appropriate, accurate, and acceptable diagnosis for people who are overly concerned about their pain.Preparation of this manuscript was facilitated by support from a Canadian Institutes of Health Research (CIHR) Canada Research Chair in Health Psychology awarded to Dr Katz and a CIHR Canada Graduate Master’s Award to Samantha Fashler

Trametinib-Induced Epidermal Thinning Accelerates a Mouse Model of Junctional Epidermolysis Bullosa

Junctional epidermolysis bullosa (JEB) patients experience skin and epithelial fragility due to a pathological deficiency in genes associated with epidermal adhesion. Disease severity ranges from post-natal lethality to localized skin involvement with persistent blistering followed by granulation tissue formation and atrophic scarring. We evaluated the potential of utilizing Trametinib, an MEK inhibitor previously shown to target fibrosis, with and without the documented EB-anti-fibrotic Losartan for reducing disease severity in a mouse model of JEB; Lamc2jeb mice. We found that Trametinib treatment accelerated disease onset and decreased epidermal thickness, which was in large part ameliorated by Losartan treatment. Interestingly, a range of disease severity was observed in Trametinib-treated animals that tracked with epidermal thickness; those animals grouped with higher disease severity had thinner epidermis. To examine if the difference in severity was related to inflammation, we conducted immunohistochemistry for the immune cell markers CD3, CD4, CD8, and CD45 as well as the fibrotic marker αSMA in mouse ears. We used a positive pixel algorithm to analyze the resulting images and demonstrated that Trametinib caused a non-significant reduction in CD4 expression that inversely tracked with increased fibrotic severity. With the addition of Losartan to Trametinib, CD4 expression was similar to control. Together, these data suggest that Trametinib causes a reduction in both epidermal proliferation and immune cell infiltration/proliferation, with concurrent acceleration of skin fragility, while Losartan counteracts Trametinib’s adverse effects in a mouse model of JEB

Effects of perioperative clinical hypnosis on heart rate variability in patients undergoing oncologic surgery: secondary outcomes of a randomized controlled trial

IntroductionClinical hypnosis has been proposed for post-surgical pain management for its potential vagal-mediated anti-inflammatory properties. Evidence is needed to understand its effectiveness for post-surgical recovery. Iin this secondary outcome study, it was hypothesized that surgical oncology patients randomized to receive perioperative clinical hypnosis (CH) would demonstrate greater heart-rate variability (HRV) during rest and relaxation at a 1-month post-surgery assessment compared to a treatment-as-usual group (TAU).MethodsAfter REB approval, trial registration and informed consent, 92 participants were randomized to receive CH (n = 45) or TAU (n = 47). CH participants received a CH session before surgery and during post-surgical in-hospital stay HRV was assessed during rest (5 min) and relaxation (10 min) before and 1-month after surgery. Pain intensity was obtained using a 0–10 numeric rating scale pre and post 1-week and 1-month post surgery.ResultsOne month after surgery, HRV was significantly higher in CH group (n = 29) during rest and relaxation (both p < 0.05, d = 0.73) than TAU group (n = 28). By contrast, rest and relaxation HRV decreased from pre- to 1-month post-surgery for the TAU (both p < 0.001, d > 0.48) but not the CH group. Pain intensity increased from pre-surgery to 1-week post-surgery (p < 0.001, d = 0.50), and decreased from 1-week to 1-month post-surgery (p = 0.005, d = 0.21) for all participants.DiscussionThe results suggest that hypnosis prevents the deleterious effects of surgery on HRV by preserving pre-operative vagal activity. These findings underscore the potential of clinical hypnosis in mitigating the adverse effects of surgery on autonomic function and may have significant implications for enhancing post-surgical recovery and pain management strategies.Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT03730350)