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Cyclooxygenase (COX-1 & 2) pathways of lipid mediator biosynthesis during exercise recovery. A: COX-1 & 2 pathways of prostanoid biosynthesis. Free intracellular arachidonic acid (AA) substrate, mobilized from cell membrane phospholipids is converted to PGH 2 by the action of the COX-1 & 2 enzymes. PGH 2 is the precursor to the major bioactive PGs including TXA 2 , PGD 2 , PGE 2 , PGF 2α , and PGI 2 by action of specific PG synthases. B: Time-course of peripheral blood COX/PG responses during recovery from unaccustomed resistance exercise as determined by mediator lipidomic profiling (102).
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Lipid mediators are bioactive metabolites of the essential polyunsaturated fatty acids (PUFA) that play diverse roles in the initiation, self-limitation, and active resolution of inflammation. Prostaglandins, classical pro-inflammatory lipid metabolites of arachidonic acid, have long been implicated in immunological and adaptive muscle responses to...
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Oxylipins are bioactive lipid mediators synthesised from PUFA. The most well-known oxylipins are the eicosanoids derived from arachidonic acid (ARA), and many of them influence cardiac physiology in health and disease. Oxylipins are also formed from other n -3 and n -6 PUFA such as α -linolenic acid (ALA), EPA, DHA and linoleic acid (LA), but funda...
Abstract Lipid mediators including classical arachidonic acid‐derived eicosanoids (e.g. prostaglandins and leukotrienes) and more recently identified specialized pro‐resolving‐mediator metabolites of the omega‐3 fatty acids play essential roles in initiation, self‐limitation, and active resolution of acute inflammatory responses. In this study, we...
Background
Most forms of cancer, including hepatocellular carcinoma (HCC), are associated with varying degrees of chronic inflammation. The association between the expression of eicosanoids, which are bioactive lipid mediators of inflammation, and HCC remains unknown. The aim of this study was to measure serum and hepatic eicosanoids in a mouse mod...
Lipidomics is the area of study dedicated to the comprehensive analysis and characterization of the functions and metabolism of lipids in biological samples. One of the most comprehensively studied classes of lipids is polyunsaturated fatty acids (PUFAs). Eicosanoids are a series of bioactive lipid mediators that are metabolized from PUFAs and gene...
Over the last years, many microRNAs (miRNAs) have been identified that regulate the formation of bioactive lipid mediators such as prostanoids and leukotrienes. Many of these miRNAs are involved in complex regulatory circuits necessary for the fine-tuning of biological functions including inflammatory processes or cell growth. A better understandin...
Citations
... Successful resolution requires the apoptosis of neutrophils, arrest of leukocyte infiltration, and macrophage efferocytosis of apoptotic cells [49,50]. This process is mediated, in part, by lipid mediators [51]. Several classes of mediators with anti-inflammatory and pro-resolving bioactivity actively promote the return to a non-inflamed state. ...
... It is now recognized that the resolution of inflammation is an active process, and not a passive waning of pro-inflammatory signals [150]. As alluded to previously, lipid mediators play an important role in mediating local and systemic inflammatory responses [51]. At basal conditions, these mediators sourced from polyunsaturated fatty acids (PUFAs) primarily coming from the diet are suspended as phospholipids in the cell membrane. ...
... The oxidation of the mobilized PUFA substrate can occur through three major pathways: (1) cyclooxygenase (COX), (2) lipoxygenase (LOX), and (3) epoxygenase-catalyzed by cytochrome P450 (CYP). Through these pathways, hundreds of lipid mediators can be synthesized [51]. The early stages of tissue injury are dominated by pro-inflammatory lipid mediators. ...
Understanding the intricate mechanisms governing the cellular response to resistance exercise is paramount for promoting healthy aging. This narrative review explored the age-related alterations in recovery from resistance exercise, focusing on the nuanced aspects of exercise-induced muscle damage in older adults. Due to the limited number of studies in older adults that attempt to delineate age differences in muscle discovery, we delve into the multifaceted cellular influences of chronic low-grade inflammation, modifications in the extracellular matrix, and the role of lipid mediators in shaping the recovery landscape in aging skeletal muscle. From our literature search, it is evident that aged muscle displays delayed, prolonged, and inefficient recovery. These changes can be attributed to anabolic resistance, the stiffening of the extracellular matrix, mitochondrial dysfunction, and unresolved inflammation as well as alterations in satellite cell function. Collectively, these age-related impairments may impact subsequent adaptations to resistance exercise. Insights gleaned from this exploration may inform targeted interventions aimed at enhancing the efficacy of resistance training programs tailored to the specific needs of older adults, ultimately fostering healthy aging and preserving functional independence.
... Depending on the metabolic context, oxylipins can function as beneficial signaling agents or mediators of inflammation, immune dysfunction, and disease [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. A significant proportion of the physiological and immune system effects from n-6 and n-3 PUFAs are mediated through these oxidized metabolites (i.e., lipid mediators) and have emerged as sensitive indicators of metabolic change in nutrition-based interventions [9,11,15,18,[28][29][30] or in various disease states [10,[20][21][22][23][24][25][26][27]. ...
... Exercise-induced muscle tissue injury, inflammation, and metabolic stress prompt an innate immune response. Lipid mediators are involved in initiating, mediating, and resolving this process [16][17][18][29][30][31]. ...
Mangoes have a unique nutrient profile (carotenoids, polyphenols, sugars, and vitamins) that we hypothesized would mitigate post-exercise inflammation. This study examined the effects of mango ingestion on moderating exercise-induced inflammation in a randomized crossover trial with 22 cyclists. In random order with trials separated by a 2-week washout period, the cyclists ingested 330 g mango/day with 0.5 L water or 0.5 L of water alone for 2 weeks, followed by a 2.25 h cycling bout challenge. Blood and urine samples were collected pre- and post-2 weeks of supplementation, with additional blood samples collected immediately post-exercise and 1.5-h, 3-h, and 24 h post-exercise. Urine samples were analyzed for targeted mango-related metabolites. The blood samples were analyzed for 67 oxylipins, which are upstream regulators of inflammation and other physiological processes. After 2 weeks of mango ingestion, three targeted urine mango-related phenolic metabolites were significantly elevated compared to water alone (interaction effects, p ≤ 0.003). Significant post-exercise increases were measured for 49 oxylipins, but various subgroup analyses showed no differences in the pattern of change between trials (all interaction effects, p > 0.150). The 2.25 h cycling bouts induced significant inflammation, but no countermeasure effect was found after 2 weeks of mango ingestion despite the elevation of mango gut-derived phenolic metabolites.
... [22][23][24] COX-1 is constitutively expressed, allowing for immediate PG synthesis after release of arachidonic acid, 24,25 whereas COX-2 expression is induced by inflammation and is associated with pain. [26][27][28][29] The analgesic properties of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, 30 are due to the inhibition of COX-1 and COX-2 and prevention of PG synthesis. ...
BACKGROUND
Pelvic floor muscle injury is a common consequence of vaginal childbirth. Nonsteroidal anti-inflammatory drugs are widely used postpartum analgesics. Multiple studies have reported negative effects of these drugs on limb muscle regeneration, but their impact on pelvic floor muscle recovery following birth injury has not been explored.
OBJECTIVE
Using a validated rat model, we assessed the effects of nonsteroidal anti-inflammatory drug on acute and longer-term pelvic floor muscle recovery following simulated birth injury.
STUDY DESIGN
Three-month old Sprague Dawley rats were randomly assigned to the following groups: (1) controls, (2) simulated birth injury, (3) simulated birth injury+nonsteroidal anti-inflammatory drug, or (4) nonsteroidal anti-inflammatory drug. Simulated birth injury was induced using a well-established vaginal balloon distension protocol. Ibuprofen was administered in drinking water (0.2 mg/mL), which was consumed by the animals ad libitum. Animals were euthanized at 1, 3, 5, 7, 10, and 28 days after birth injury/ibuprofen administration. The pubocaudalis portion of the rat levator ani, which, like the human pubococcygeus, undergoes greater parturition-associated strains, was harvested (N=3–9/time point/group). The cross-sectional areas of regenerating (embryonic myosin heavy chain⁺) and mature myofibers were assessed at the acute and 28-day time points, respectively. The intramuscular collagen content was assessed at the 28-day time point. Myogenesis was evaluated using anti-Pax7 and anti-myogenin antibodies to identify activated and differentiated muscle stem cells, respectively. The overall immune infiltrate was assessed using anti-CD45 antibody. Expression of genes coding for pro- and anti-inflammatory cytokines was assessed by quantitative reverse transcriptase polymerase chain reaction at 3, 5, and 10 days after injury.
RESULTS
The pubocaudalis fiber size was significantly smaller in the simulated birth injury+nonsteroidal anti-inflammatory drug compared with the simulated birth injury group at 28 days after injury (P<.0001). The median size of embryonic myosin heavy chain⁺ fibers was also significantly reduced, with the fiber area distribution enriched with smaller fibers in the simulated birth injury+nonsteroidal anti-inflammatory drug group relative to the simulated birth injury group at 3 days after injury (P<.0001), suggesting a delay in the onset of regeneration in the presence of nonsteroidal anti-inflammatory drugs. By 10 days after injury, the median embryonic myosin heavy chain⁺ fiber size in the simulated birth injury group decreased from 7 days after injury (P<.0001) with a tight cross-sectional area distribution, indicating nearing completion of this state of regeneration. However, in the simulated birth injury+nonsteroidal anti-inflammatory drug group, the size of embryonic myosin heavy chain⁺ fibers continued to increase (P<.0001) with expansion of the cross-sectional area distribution, signifying a delay in regeneration in these animals. Nonsteroidal anti-inflammatory drugs decreased the muscle stem cell pool at 7 days after injury (P<.0001) and delayed muscle stem cell differentiation, as indicated by persistently elevated number of myogenin⁺ cells 7 days after injury (P<.05). In contrast, a proportion of myogenin⁺ cells returned to baseline by 5 days after injury in the simulated birth injury group. The analysis of expression of genes coding for pro- and anti-inflammatory cytokines demonstrated only transient elevation of Tgfb1 in the simulated birth injury+nonsteroidal anti-inflammatory drug group at 5 but not at 10 days after injury. Consistently with previous studies, nonsteroidal anti-inflammatory drug administration following simulated birth injury resulted in increased deposition of intramuscular collagen relative to uninjured animals. There were no significant differences in any outcomes of interest between the nonsteroidal anti-inflammatory drug group and the unperturbed controls.
CONCLUSION
Nonsteroidal anti-inflammatory drugs negatively impacted pelvic floor muscle regeneration in a preclinical simulated birth injury model. This appears to be driven by the negative impact of these drugs on pelvic muscle stem cell function, resulting in delayed temporal progression of pelvic floor muscle regeneration following birth injury. These findings provide impetus to investigate the impact of postpartum nonsteroidal anti-inflammatory drug administration on muscle regeneration in women at high risk for pelvic floor muscle injury.
... Interindividual variability in biomarker responses to eccentric exercise-induced muscle damage due to SNPs may limit the efficacy of nutritional interventions. Lipid mediators generated from DHA and EPA have been hypothesized to enhance muscle regeneration by regulating the inflammatory response to muscle injury, but definitive evidence in exercise-based studies is lacking 20,38,39 . Daily intraperitoneal injection of DHA-derived resolvin D1 (RvD1) in aged mice suppressed inflammatory cytokine expression and improved recovery of muscle function and was advanced as a promising treatment of muscular injuries and pain in the elderly 39 . ...
Abstract This study determined if 18 days of supplementation with blueberries (BL) compared to placebo (PL) could mitigate muscle soreness and damage and improve inflammation resolution in untrained adults (n = 49, ages 18–50 years) after engaging in a 90-min bout of “weekend warrior” eccentric exercise. The BL freeze dried supplement provided 1 cup of fresh blueberries per day equivalent with 805 mg/day total phenolics and 280 mg/day anthocyanins. Urine levels of eight BL gut-derived phenolics increased after 14- and 18-days supplementation with 83% higher concentrations in BL vs. PL (p
... A complex crosstalk between cells exists and is regulated by numerous mediators, such as peptides (e.g., cytokines, chemokines), reactive oxygen species (e.g., superoxide anion, hydrogen peroxide), amino acid derivatives (e.g., histamine, nitric oxide), enzymes (e.g., matrix peroxidases) and lipid mediators (e.g., prostaglandins, leukotrienes, endocannabinoids, platelet-activating factor, sphingolipids) released by the resident cell populations depending on the cell types, anatomical site and inflammatory stimulus [16,17]. The latter, which are autocrine/paracrine signaling molecules, have a key role in muscle homeostasis and the resolution of inflammation caused by exercise [3,17]. ...
... Briefly, by the action of phospholipases A 2 (PLA 2 s), membrane glycerol-phospholipids are converted to their lyso-analogs, releasing the fatty acid esterified in the sn-2 position of the glycerol backbone. Arachidonic acid (AA; 20:4n-6), which is the most predominant polyunsaturated fatty acid, is esterified in the sn-2 position of the phosphatidylinositol and/or phosphatidylcholine and also regulates the physical properties of the membranes [3,18,19], is consequently enzymatically converted into a variety of eicosanoid mediators. The n-3 PUFA eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) are also released and subsequently give rise to the less inflammatory and pro-resolving lipid mediators. ...
... As a result, the products of the COX reactions are relatable to the substrate availability [19]. The prostanoids have several receptors on the muscle that regulate their actions through different mechanisms, contributing to processes such as myoblast proliferation, differentiation, fusion, migration and myotube hypertrophy [3]. ...
Lipid mediators are a class of signaling molecules that play important roles in various physiological processes, including inflammation, blood pressure regulation, and energy metabolism. Exercise has been shown to affect the production and metabolism of several types of lipid mediators, including prostaglandins, leukotrienes, sphingolipids, platelet-activating factors and endocannabinoids. Eicosanoids, which include prostaglandins and leukotrienes, are involved in the regulation of inflammation and immune function. Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, are involved in the regulation of pain, mood, and appetite. Pro-resolving lipid mediators are involved in the resolution of inflammation. Sphingolipids have a role in the function of skeletal muscle during and after exercise. There are many studies that have examined the effects of exercise on the production and release of these and other lipid mediators. Some of these studies have focused on the effects of exercise on inflammation and immune function, while others have examined the effects on muscle function and metabolism. However, much less is known about their involvement in the phenomenon of exercise-induced muscle damage that follows after intense or unaccustomed exercise.
... A decrease in CD4 + , CD8 + , CD19 + , and CD56 + lymphocytes during the recovery period (1-2 h) post high-intensity exercise indicates the immunosuppressive effect, which is also known as an open-window impact [3,10,11]. Inflammation is a primary immune response involved in the prevention of infection, damage, and noxious conditions for the maintenance of tissue repair and homeostasis [12,13]. Reportedly, inflammation-related markers such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 have been found to have considerably increased post strenuous exercise [14][15][16]. ...
Reportedly, strenuous endurance exercise can depress the immune system and induce inflammation and muscle damage. Therefore, this double-blinded, matched-pair study aimed to investigate the impact of vitamin D3 supplementation on immune response (leukocyte, neutrophil, lymphocyte, CD4+, CD8+, CD19+, and CD56+ counts), inflammatory profile (TNF-α and IL-6), muscle damage (CK and LDH levels), as well as aerobic capacity after strenuous endurance exercise in 18 healthy men taking 5000 IU of vitamin D3 (n = 9) or placebo (n = 9) daily for 4 weeks. Total and differential blood leukocyte counts, levels of cytokines, and muscle damage biomarkers were determined before, immediately after, and 2, 4, and 24 h after exercise. The IL-6, CK, and LDH levels were significantly lower in vitamin D3 group at 2, 4, and 24 h post exercise (p < 0.05). Maximal and average heart rates during exercise were also significantly lower (p < 0.05). In the vitamin D3 group, the CD4+/CD8+ ratio after 4 weeks of supplementation was only significantly lower at post-0 than at baseline and significantly higher at post-2 than at baseline and post-0 (all p < 0.05). Taken together, 5000 IU of daily vitamin D3 supplementation for 4 weeks exhibited positive effects in terms of increased blood 25(OH)D levels, CD4+/CD8+ ratio (immune response), and aerobic capacity while inhibiting inflammatory cytokines and CK and LDH (muscle damage) in people performing strenuous endurance exercise.
... When reviewing the literature, we found that several of the 43 metabolites identified in this article are involved in the injury repair process. For example, prostaglandin E1 has been reported to regulate blood flow, vascular permeability, and neutrophil migration as a chemokine [27], and 13S-hydroxyoctadecadienoic acid regulates intercellular adhesion as inflammation progresses [28]. Notably, the changes in prostaglandin E1, 15-HETE, 18-HETE, 13Shydroxyoctadecadienoic acid, and medroxyprogesterone exhibited similar trends, which is in agreement with the research of Markworth et al. [27]. ...
... For example, prostaglandin E1 has been reported to regulate blood flow, vascular permeability, and neutrophil migration as a chemokine [27], and 13S-hydroxyoctadecadienoic acid regulates intercellular adhesion as inflammation progresses [28]. Notably, the changes in prostaglandin E1, 15-HETE, 18-HETE, 13Shydroxyoctadecadienoic acid, and medroxyprogesterone exhibited similar trends, which is in agreement with the research of Markworth et al. [27]. The above results indicated that the metabolites identified in the present study are highly correlated with skeletal muscle injury and can be applied for the wound age estimation. ...
Wound age estimation is one of the most challenging and indispensable issues for forensic pathologists. Although many methods based on physical findings and biochemical tests can be used to estimate wound age, an objective and reliable method for inferring the time interval after injury remains difficult. In the present study, endogenous metabolites of contused skeletal muscle were investigated to estimate the time interval after injury. Animal model of skeletal muscle injury was established using Sprague–Dawley rat, and the contused muscles were sampled at 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 h postcontusion (n = 9). Then, the samples were analysed using ultraperformance liquid chromatography coupled with high-resolution mass spectrometry. A total of 43 differential metabolites in contused muscle were determined by metabolomics method. They were applied to construct a two-level tandem prediction model for wound age estimation based on multilayer perceptron algorithm. As a result, all muscle samples were eventually divided into the following subgroups: 4, 8, 12, 16–20, 24–32, 36–40, and 44–48 h. The tandem model exhibited a robust performance and achieved a prediction accuracy of 92.6%, which was much higher than that of the single model. In summary, the multilayer perceptron–multilayer perceptron tandem machine-learning model based on metabolomics data can be used as a novel strategy for wound age estimation in future forensic casework.
Key Points
... Several review papers have concluded that increased intake of blueberries, anthocyanins, and polyphenols in general may have a small, variable, or null effect on mitigating exercise-induced muscle soreness, damage, and dysfunction [29][30][31][32][33][34][35][36]. Lipid mediators generated from DHA and EPA have been hypothesized to enhance muscle regeneration by regulating the inflammatory response to muscle injury, but definitive evidence in exercise-based studies is lacking [20,37,38]. Daily intraperitoneal injection of DHA-derived resolvin D1 (RvD1) in aged mice suppressed inflammatory cytokine expression and improved recovery of muscle function and was advanced as a promising treatment of muscular injuries and pain in the elderly [38]. ...
This study determined if 18 days of supplementation with blueberries (BL) compared to placebo (PL) could mitigate muscle soreness and damage and improve inflammation resolution in untrained adults (n = 49, ages 30–65 y) after engaging in a 90-minute bout of “weekend warrior” eccentric exercise. The BL freeze dried supplement provided 1 cup of fresh blueberries per day equivalent with 805 mg/d total phenolics and 280 mg/d anthocyanins. Urine levels of eight BL gut-derived phenolics increased after 14- and 18-days supplementation with 83% higher concentrations in BL vs. PL (p < 0.001). The 90-min exercise bout caused significant muscle soreness and damage during 4d of recovery and a decrease in exercise performance with no significant differences between PL and BL. Plasma oxylipins (n = 76) were identified and grouped by fatty acid substrates and enzyme systems. Linoleic acid (LA) oxylipins generated from cytochrome P450 (CYP) (9,10-, 12,13-dihydroxy-9Z-octadecenoic acids) (diHOMEs) were lower in BL vs. PL (treatment effect, p = 0.051). A compositive variable of 9 plasma hydroxydocosahexaenoic acids (HDoHEs) generated from docosahexaenoic acid (DHA, 22:6) and lipoxygenase (LOX) was significantly higher in BL vs. PL (treatment effect, p = 0.008). The composite variable of plasma 14-HDoHE, 17-HDoHE, and the eicosapentaenoic acid (EPA)-derived oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE) (specialized pro-resolving lipid mediators, SPM, intermediates) was significantly higher in BL vs PL (treatment effect, p = 0.014). Pearson correlations showed positive relationships between post-exercise DHA-LOX HDoHEs and SPM intermediates with urine blueberry gut-derived phenolics (r = 0.324, p = 0.023, and r = 0.349, p = 0.015, respectively). These data indicate that 18d intake of 1 cup/d blueberries compared to PL was linked to a reduction in pro-inflammatory diHOMES and sustained elevations in DHA- and EPA-derived anti-inflammatory oxylipins in response to a 90-min bout of unaccustomed exercise by untrained adults.
... In parallel, a tightly regulated and time-dependent recruitment of immune cells occurs, releasing inflammatory factors (e.g., TNF-α, IL-6), which also have the capacity to promote SC activation and proliferation. Later in the regeneration process, immune cells together with FAP cells contribute to the removal of cell debris and necrotic tissue [12][13][14]. This response is followed by the clearance of proinflammatory cytokines and the recruitment of antiinflammatory immune cells, promoting SC differentiation, tissue repair, and the return of tissue homeostasis [15][16][17]. ...
... There is emerging evidence that bioactive lipids derived from n-3 and n-6 PUFAs play a key role in the initiation and resolution of the inflammatory response [12,43]. After a muscle injury, n-3 and n-6 PUFAs are rapidly released from immune cell membrane phospholipids via phospholipase enzymes and metabolized via enzymatic reactions to the lipid mediators oxylipins and endocannabinoids [44]. ...
... After a muscle injury, n-3 and n-6 PUFAs are rapidly released from immune cell membrane phospholipids via phospholipase enzymes and metabolized via enzymatic reactions to the lipid mediators oxylipins and endocannabinoids [44]. During the early stages of injury, the classical n-6 PUFA-derived lipid mediators are synthesized and released, promoting acute inflammation by regulating local blood flow, vascular permeability, cytokine production, and leukocyte chemotaxis [12]. Later, a shift in the profile of these mediators results in the generation of oxylipins and endocannabinoids mainly derived from n-3 PUFAs, whose functions are to actively resolve and terminate inflammation, leading to tissue regeneration and return to homeostasis [45,46]. ...
Skeletal muscle is the largest tissue in the human body, comprising approximately 40% of body mass. After damage or injury, a healthy skeletal muscle is often fully regenerated; however, with aging and chronic diseases, the regeneration process is usually incomplete, resulting in the formation of fibrotic tissue, infiltration of intermuscular adipose tissue, and loss of muscle mass and strength, leading to a reduction in functional performance and quality of life. Accumulating evidence has shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and their lipid mediators (i.e., oxylipins and endocannabinoids) have the potential to enhance muscle regeneration by positively modulating the local and systemic inflammatory response to muscle injury. This review explores the process of muscle regeneration and how it is affected by acute and chronic inflammatory conditions, focusing on the potential role of n-3 PUFAs and their derivatives as positive modulators of skeletal muscle healing and regeneration.
... Transcriptional regulation through transcription factors such as, C/EBPβ [107], STAT3 [108], NFIX [109], PPARγ [84] or BACH1 [110] and epigenetic changes [111][112][113] have been shown to contribute to the macrophage switch modifying macrophage gene expression, products and function. As a result of transcriptional changes, several signalling pathways involving cytokines [interleukin-6 (IL-6), IL-10], growth factors (IGF1) and lipid mediators (RvD1, RvD2, RvE1) [10,114] enhance further modifications necessary for the macrophage switch. ...
Inflammation is an essential immune response critical for responding to infection, injury and maintenance of tissue homeostasis. Upon injury, regenerative inflammation promotes tissue repair by a timed and coordinated infiltration of diverse cell types and the secretion of growth factors, cytokines and lipids mediators. Remarkably, throughout evolution as well as mammalian development, this type of physiological inflammation is highly associated with immunosuppression. For instance, regenerative inflammation is the consequence of an in situ macrophage polarization resulting in a transition from pro‐inflammatory to anti‐inflammatory/pro‐regenerative response. Immune cells are the first responders upon injury, infiltrating the damaged tissue and initiating a pro‐inflammatory response depleting cell debris and necrotic cells. After phagocytosis, macrophages undergo multiple coordinated metabolic and transcriptional changes allowing the transition and dictating the initiation of the regenerative phase. Differences between a highly efficient, complete ad integrum tissue repair, such as, acute skeletal muscle injury, and insufficient regenerative inflammation, as the one developing in Duchenne Muscular Dystrophy (DMD), highlight the importance of a coordinated response orchestrated by immune cells. During regenerative inflammation, these cells interact with others and alter the niche, affecting the character of inflammation itself and, therefore, the progression of tissue repair. Comparing acute muscle injury and chronic inflammation in DMD, we review how the same cells and molecules in different numbers, concentration and timing contribute to very different outcomes. Thus, it is important to understand and identify the distinct functions and secreted molecules of macrophages, and potentially other immune cells, during tissue repair, and the contributors to the macrophage switch leveraging this knowledge in treating diseases.
