immune thrombocytopenia, statins, NAC - brief notes

 

A brief review on how statins could be used to treat immune thrombocytopenia (ITP), an autoimmune disease:

Nazy and Cuker (2018) - Statins for high cholesterol … and for low platelets? - https://doi.org/10.1182/blood-2018-01-824888

"Megakaryocytes in ITP patients show impaired maturation and signs of degradation due to defects in the megakaryocytes and their environment.⁷  Among the cells in the BM [bone marrow] niche implicated in supporting megakaryopoiesis and thrombopoiesis are the BM EPCs [endothelial progenitor cells], ...

Treatments that induce platelet production by enhancing the BM microenvironment could be beneficial for corticosteroid-resistant ITP. Atorvastatin is a widely used drug for the treatment of primary hypercholesterolemia and mixed dyslipidemia by inhibiting 3-hydroxy-3methyl-glutaryl-coenzyme A reductase. Among its activities, it is known to improve the mobilization and function of EPCs. Recently, Shi et al showed the effectiveness of atorvastatin in increasing the functional characteristics of EPCs from patients with poor graft function after allo-HSCT.⁸  In the current study, Kong et al found that atorvastatin increased the total number of BM EPCs in corticosteroid-resistant ITP compared with untreated cells (2.3- ± 0.4-fold; P = .003). In addition, when atorvastatin was used, the function of BM EPCs from corticosteroid-resistant ITP was improved by downregulating the p38 MAPK pathway (0.8 ± 0.1-fold; P = .003) and upregulating the Akt pathway (2.5- ± 0.3-fold; P = .0002). These functional improvements led to increased megakaryocyte numbers (1.6- ± 0.2-fold; P = .02) and platelet release (2.6- ± 0.6-fold; P = .02) (see figure panel B). Similar effects were observed with other p38 inhibitors and N-acetyl-l-cysteine, a reactive oxygen species scavenger." 

A previous post on beneficial effects of vibration on bone marrow mesenchymal stem cells pointed out  the role of osteoblasts in maintaining the hematopoietic niche. Celiac and other autoimmune diseases can cause osteoporosis. Could vibration be used to treat autoimmune diseases? Of course, appropriate dosing would need to be determined - if there are 'good vibrations', then it seems there could be be bad ones, also (in terms vibration frequency and duration of application).

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 As it turns out, there was a trial of whole body vibration therapy for rheumatoid arthritis. The treatment  - (30 Hz, amplitude: 3mm), 15min/session, 2 sessions/week -  improved bone mineral density and lessened fatigue,  but there was no change in RA disease activity, unfortunately.

Prioreschi et al. (2016) - In Patients with Established RA, Positive Effects of a Randomised Three Month WBV Therapy Intervention on Functional Ability, Bone Mineral Density and Fatigue Are Sustained for up to Six Months - https://pubmed.ncbi.nlm.nih.gov/27073832/

It is a good thing the vibration therapy did not worsen the study participants' RA symptoms:

Zhao (2017) - Low magnitude high frequency vibration promotes adipogenic differentiation of bone marrow stem cells via P38 MAPK signal - https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172954

"Altogether, this indicates that p38 MAPK is activated during adipogenesis of BMSCs, and this is promoted by LMHFV [low frequency high magnitude vibration - (0.3g, 40 Hz, amplitude: 50μm), 15min/d]. Our results demonstrating that specific parameters of LMHFV promotes adipogenesis of MSCs and enhances osteogenesis, highlights an unbeneficial side effect of vibration therapy used for preventing obesity and osteoporosis.

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Mechanical forces have also been reported to activate the p38 pathway.  

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Previous studies which demonstrated a certain vibration strengthened osteogenesis while suppressing adipogenesis, were studying this indifferent cellular environments than the environment we studied ...

We tested in vitro LMHFV promoted adipogenesis of BMSCs. However, whether this same effect could be duplicated under different experimental conditions in vitro and in vivo, is unknown. Increase in the number of adipocytes and lipid accumulation are both important factors that induce obesity[24]. Similarly, osteoporosis often occured when adipose tissue in marrow cavity grows and altered the balance between fat and bone[32]. Thus, before LMHFV could be safely used to treat these clinical problems, there is still much work to be done, both in vitro and vivo."

As usual, more studies are needed ... and dosing seems really important - 

Clark and Dean (2012) - The p38 MAPK Pathway in Rheumatoid Arthritis: A Sideways Look
https://openrheumatologyjournal.com/VOLUME/6/PAGE/209/FULLTEXT/

"Under most experimental conditions, negative feedback mechanisms ensure that p38 activation in response to a pro-inflammatory agonist is transient. In many cases the response is also followed by a refractory condition, in which the kinase pathway responds weakly to the same agonist or a different pro-inflammatory agonist (tolerance or cross-tolerance)."