Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 minutes twice daily reduced inflammation and improved pain, two weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch vs. no stretch for 48 hours, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue.
There is growing interest in developing non-pharmacological treatments that could boost natural defenses against cancer and contribute to primary and secondary cancer prevention. Recent studies have shown that gentle daily stretching for 10 minutes can reduce local connective tissue inflammation and fibrosis. Because mechanical factors within the stroma can influence the tumor microenvironment, we hypothesized that stretching would reduce the growth of tumors implanted within locally stretched tissues and tested this hypothesis in a mouse orthotopic breast cancer model. Female FVB mice (N = 66) underwent bilateral injection of p53/PTEN double-null primary mouse mammary tumor cells into the third mammary fat pad. Mice were randomized to stretch vs. no stretch, and treated for 10 minutes once a day, for four weeks. Tumor volume at end-point was 52% smaller in the stretch group, compared to the no-stretch group (p < 0.001) in the absence of any other treatment. Cytotoxic immune responses were activated and levels of Specialized Pro-Resolving Mediators were elevated in the stretch group. These results suggest a link between immune exhaustion, inflammation resolution and tumor growth. Stretching is a gentle, non-pharmacological intervention that could become an important component of cancer treatment and prevention.
ObjectiveAlthough physical therapy can help preserve mobility in patients with systemic sclerosis (SSc), stretching has not been used systematically as a treatment to prevent or reverse the disease process. We previously showed in rodent models that stretching promotes the resolution of connective tissue inflammation and reduces new collagen formation after injury. Here, we tested the hypothesis that stretching would impact scleroderma development using a mouse sclerodermatous graft-versus-host disease (sclGvHD) model.MethodsThe model consists in the adoptive transfer (allogeneic) of splenocytes from B10.D2 mice (graft) into Rag2−/− BALB/c hosts (sclGvHD), resulting in skin inflammation followed by fibrosis over 4 weeks. SclGvHD mice and controls were randomized to stretching in vivo for 10 min daily versus no stretching.ResultsWeekly ultrasound measurements of skin thickness and subcutaneous tissue mobility in the back (relative tissue displacement during passive trunk motion) successfully captured the different phases of the sclGvHD model. Stretching reduced skin thickness and increased subcutaneous tissue mobility compared to no stretching at week 3. Stretching also reduced the expression of CCL2 and ADAM8 in the skin at week 4, which are two genes known to be upregulated in both murine sclGvHD and the inflammatory subset of human SSc. However, there was no evidence that stretching attenuated inflammation at week 2.ConclusionDaily stretching for 10 min can improve skin thickness and mobility in the absence of any other treatment in the sclGvHD murine model. These pre-clinical results suggest that a systematic investigation of stretching as a therapeutic modality is warranted in patients with SSc.
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Type I immediate hypersensitivity to platelet proteins may be an allergic transfusion reaction mechanism. Prior sensitization to human proteins is not required for basophil responses to platelet proteins. Further study into the relative contributions of hypersensitivity to platelet versus plasma proteins in transfusion is warranted.
Background: A general understanding of allergic transfusion reaction (ATR) mechanisms remains elusive. Various hypotheses invoke proteins, small molecules, mitochondria, or microparticles that may be plasma or platelet derived and suggest antibody dependent or independent mechanisms. There has been no systematic comparison of these proposed mechanisms. The aim of this study is to characterize the mechanistic determinants of ATRs. Methods: Basophil enriched cell suspensions were collected from healthy donors (n=8). Basophil histamine release was measured in response to platelet-derived components: platelet component supernatant (plasma), platelet lysate, and manipulated platelet lysates were examined to characterize the unknown allergic stimuli. Lysate manipulations were: 1) dialysis against a 3,500 molecular weight cutoff membrane, 2) butanol/DIPE delipidation, 3) trypsinization with immobilized trypsin beads, 4) mild heat denaturation at 47˚C for 20 minutes, and 5) ultracentrifugation at 200,000 gfor 1hr. Immunoglobulin-dependent mechanisms were investigated through lactic acid immunoglobulin depletion from the basophil cell surface and signaling inhibition with ibrutinib. Histamine release from magnetic bead isolated platelet mitochondria was compared to platelet lysate with or without DNase treatment. Platelet lysate histamine content represented an average of <4% of total basophil histamine content. The residual histamine originating from platelet lysate was subtracted from post-reaction histamine concentrations. Atopic histories and grass, tree, and weed-specific IgE were measured in basophil donors. Results: Robust, dose-responsive histamine release to platelet lysate was observed in two of eight healthy donors. No histamine release was observed with plasma. Reactivity did not correlate with the clinical allergic phenotype, and reactive donors were nulliparous and had no prior transfusion. Trypsin treatment of platelet lysate reduced histamine release by 39% (p=0.008). Delipidation of platelet lysate decreased histamine release by 20% (p=0.051). Dialysis, ultracentrifugation, and mild heat denaturation of platelet lysate did not significantly affect histamine release, compared to unmanipulated platelet lysate. To investigate the immunoglobulin dependence of basophil activation, in separate experiments we 1) depleted immunoglobulins, including IgE, from the basophil cell surface, and 2) inhibited immunoglobulin-mediated intracellular signaling with ibrutinib. Histamine release in response to platelet lysate significantly decreased in both cases. Finally, isolated platelet mitochondria induced minimal basophil histamine release, and DNase treatment did not inhibit activation of basophils by platelet lysate. Conclusion: Type I immediate hypersensitivity to platelet, not plasma, proteins is a primary mechanism for ATRs. Small molecules, microparticles, and mitochondria are not significant contributors to ATRs in this human basophil model. Prior sensitization to human proteins is not required for basophil responses to platelet proteins. Donor variability and storage conditions that promote accumulation of soluble platelet-derived proteins may contribute to ATRs. Disclosures No relevant conflicts of interest to declare.
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