Spatiotemporal phosphoprotein distribution and associated cytokine response of a traumatic injury

Abstract

Molecular mechanisms of wound healing have been extensively characterized, providing a better understanding of the processes involved in wound repair and offering advances in treatment methods. Both spatial and temporal investigations of injury biomarkers have helped to pinpoint significant time points and locations during the recovery process, which may be vital in managing the injury and making the appropriate diagnosis. This study addresses spatial and temporal differences of phosphoproteins found in skeletal muscle tissue following a traumatic femur fracture, which were further compared to co-localized cytokine responses. In particular, several proteins (Akt, ERK, c-Jun, CREB, JNK, MEK1, and p38) and post-translational phosphorylations (p-Akt, p-c-Jun, p-CREB, p-ERK1/2, p-MEK1, p-p38, p-GSK3α/β, p-HSP27, p-p70S6K, and p-STAT3) associated with inflammation, new tissue formation, and remodeling were found to exhibit significant spatial and temporal differences in response to the traumatic injury. Quadratic discriminant analysis of all measured responses, including cytokine concentrations from previously published findings, was used to classify temporal and spatial observations at high predictive rates, further confirming that distinct spatiotemporal distributions for total protein, phosphorylation signaling, and cytokine (IL-1α, IL-1ß, IL2, IL6, TNF-α, and MIP-1α) responses exist. Finally, phosphoprotein measurements were found to be significantly correlated to cytokine concentrations, suggesting coordinated intracellular and extracellular activity during crucial periods of repair. This study represents a first attempt to monitor and assess integrated changes in extracellular and intracellular signaling in response to a traumatic injury in muscle tissues, which may provide a framework for future research to improve both our understanding of wounds and their treatment options.

New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration

“…Furthermore, the cluster of differentiation (CD) 40 pathway was highly activated, which is known to induce a proinflammatory response via tumor necrosis factor receptor‐associated factors (TRAF2 and −3) (38). Further, pathways known to induce inflammation, such as IL2 and TNF‐a signaling pathways (39), were activated in response to treatment.…”

“…The OncoFinder method revealed that the CD40, TNF‐a, and IL2 signaling pathways were activated in response to Alk4 down‐regulation. These pathways activate a proinflammatory response and thereby increase the expression of inflammatory cytokines (38, 39). We measured the expression of CD68 (Cd68) and lectin galactosidase‐binding soluble 3 (Lgals3) (inflammatory markers) with qPCR and found a significant increase in Alk4 ViM‐treated muscles (Fig.…”

Localized cytokine responses to total knee arthroplasty and total knee revision complications

“…The tissue-level cytokine response may add further understanding of the localized environment and could give insight into tissue health that would aid clinicians in the management of these post-surgical complications through surgical debridement. Tissue-level cytokines have been measured with respect to spatial gradients in traumatic injury [16][17][18], respiratory infection [19], stroke [20], and allergic response [21], and these studies provided useful information regarding the respective immune responses. These have established a basis for this study to investigate the localized implantrelated and infection-specific tissue responses.…”

“…While defining the localized response to implants and infection can be difficult [7][8][9], localized cytokine responses have been investigated for other pathological conditions. A few studies have characterized localized cytokine responses in trauma [16][17][18] and respiratory infection [19], and these studies demonstrated that the local cytokine environment differs when compared to systemically circulating levels. Currie et al [16] showed that differences in cytokine concentrations exist in skeletal muscle samples in a spatially-dependent manner using an animal model of traumatic injury.…”

Impact of Cytokines and Phosphoproteins in Response to Chronic Joint Infection

“…Radiality comparisons may reveal the most likely nodes contributing to the dysregulation observed in the IPA networks. Based on previous work in a rodent model of trauma [49], we expect that differences in nodes with low radiality between primary TKA response and aseptic or septic TKR responses may indicate the most likely causes of disruptions to normal signaling. In this study, low radiality outcomes were the most likely contributors to cell signaling dysregulation leading to chronic inflammation and infection.…”