Effects of Physical Rehabilitation on Inflammatory Markers in Patients with Chronic Diseases: A Literature Review

Chronic low-grade inflammation represents a persistent state of immune activation characterized by a continuous but moderate increase in circulating inflammatory mediators such as interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β). This subclinical inflammatory state arises as the body’s response to persistent stimuli, such as metabolic dysfunction, oxidative stress, altered microbiota, cellular aging, and excess visceral adiposity [1]. Unlike acute inflammatory processes, which are self-limiting and physiologically protective, chronic low-grade inflammation operates as a pathological backdrop capable of affecting tissues, metabolic pathways, and fundamental regulatory systems [2].

This prolonged systemic inflammatory condition is recognized as a determining factor in the pathophysiology of chronic noncommunicable diseases (NCDs), including diabetes mellitus, cardiovascular diseases, obesity, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and various metabolic disorders. Persistent activation of pro-inflammatory pathways promotes endothelial dysfunction, insulin resistance, increased protein turnover, and tissue degradation, accelerating the course of established diseases and reducing the body’s ability to maintain homeostasis (Libby, 2021). Thus, low-grade inflammation is not only a consequence of these conditions, but a central mechanism of aggravation.

The relationship between systematic inflammation and NCDs is also deeply linked to the process of immunosenescence, which involves functional decline of the immune system associated with aging. Studies show that elderly individuals have naturally elevated levels of IL-6, TNF-α, and CRP, a phenomenon called inflammaging, which increases the risk of cardiovascular and metabolic diseases, in addition to favouring structural changes in muscle, joint, and lung tissues [3]. This scenario underscores the importance of interventions capable of modulating inflammation throughout the life cycle. In addition, adipose tissue plays a crucial role in sustaining low-grade inflammation. Hypertrophied adipocytes infiltrated by M1 macrophages have high production of TNF-α, IL-6, and MCP- 1, contributing to systemic inflammation, insulin resistance, and endocrine disruption [4]. This process explains why individuals with obesity or metabolic syndrome exhibit elevated inflammatory markers and a higher risk of developing heart disease, fatty liver, osteoarticular disorders, and worsening COPD. Thus, dysfunctional adipose tissue is recognized as the largest inflammatory organ in the human body in compromised metabolic conditions.

Finally, chronic low-grade inflammation is considered a common biological link between multiple NCDs, which explains the frequent coexistence of comorbidities in the same individual. Integrative health models indicate that this sustained inflammatory state contributes to progressive deterioration of muscle function, decreased cardiorespiratory capacity, and impaired neuroendocrine function, consolidating a vicious circle between disease, sedentary lifestyle, pain, and inflammation [5]. Therefore, understanding this phenomenon is essential for the development of rehabilitation strategies and non-pharmacological interventions capable of modulating inflammatory biomarkers and mitigating the advance of chronic diseases.

Physiological mechanisms of inflammation: cytokines, metabolic pathways, and systemic impact

Chronic inflammation is anchored in a complex network of cytokines, chemokines, and humoral mediators that coordinate persistent immune responses. Among the main pro-inflammatory mediators are TNF-α, IL-1β and IL-6, produced predominantly by activated macrophages, dendritic cells and dysfunctional adipose tissue. These molecules trigger intracellular signaling cascades such as the activation of NF-κB and JAK/STAT pathways that amplify the inflammatory response and induce expression of acute phase proteins, such as CRP and fibrinogen [6]. This set of responses transforms inflammation from a local event into a systemic process with broad metabolic and organic repercussions.

The activation of the NF-κB pathway represents one of the most relevant events in the perpetuation of chronic inflammation. In pathophysiological conditions, such as obesity, insulin resistance, or tissue hypoxia, this pathway is stimulated continuously, leading to the transcription of pro-inflammatory genes and the maintenance of the baseline inflammatory state [7]. At the same time, the NLRP3 inflammasome, activated by intracellular danger signals such as reactive oxygen species, cholesterol crystals, and oxidized lipids, promotes the maturation of IL-1β and IL-18, amplifying tissue damage and favoring the development of CNCD [8]. Thus, the combination of NF-κB and inflammasomes creates a self-sustaining circuit of inflammation.

Another crucial mechanism involves the interface between inflammation and energy metabolism. Low-grade inflammation alters metabolic homeostasis through serine phosphorylation of proteins involved in insulin signaling, such as IRS-1, leading to insulin resistance and glycemic changes typical of metabolic diseases [2]. In addition, cytokines such as TNF-α and IL-6 interfere with mitochondrial function, directly affecting fatty acid oxidation and increasing the production of reactive oxygen species (ROS), which fuel a continuous cycle of inflammatory damage [9]. This metabolic imbalance creates an environment conducive to the progression of chronic diseases. At the systemic level, chronic inflammation compromises multiple physiological systems, including cardiovascular, musculoskeletal, respiratory, and neuroendocrine. In the cardiovascular system, inflammatory cytokines play a direct role in endothelial dysfunction, atherosclerotic plaque instability, and reduced nitric oxide bioavailability, increasing the risk of ischemic events [10]. In muscle tissue, persistent inflammation induces protein catabolism and reduces muscle synthesis, contributing to inflammatory sarcopenia often seen in patients with NCDs and the elderly [11]. This multisystem impact reinforces the role of inflammation as a common point between functional decline and worse clinical prognosis.

Finally, chronic inflammation also profoundly affects the neuroimmune axis. Inflammatory cytokines can cross the bloodbrain barrier and modify the function of neurotransmitters related to mood, sleep, and motivation, contributing to symptoms such as chronic fatigue, depression, and reduced exercise tolerance, often reported by patients with chronic diseases [12]. Alterations in serotonin metabolism and microglial activation reinforce the neuroendocrine impact of systemic inflammation. Thus, chronic inflammation is a complex phenomenon that integrates biological systems and plays a central role in the pathophysiology and clinical management of NCDs.

Physical rehabilitation as an immune modulator and anti-inflammatory

Physical rehabilitation has been widely recognized as an intervention capable of acting directly on the modulation of the immune system, promoting adaptations that favor a systemic antiinflammatory profile. During therapeutic exercise, skeletal muscle tissue acts as an endocrine organ capable of producing myokines such as anti-inflammatory IL-6, IL-7 and IL-15 that attenuate the activation of pro-inflammatory pathways and contribute to the regulation of energy metabolism [5]. Unlike the pro-inflammatory behavior of IL-6 in chronic states, its acute release during exercise stimulates the production of IL-10 and the IL-1 antagonist receptor (IL-1ra), reducing TNF-α and modulating pathways related to oxidative stress [13]. Thus, exercise plays a dual role: it suppresses systemic inflammation and improves adaptive immune responses.

In addition to myokines, neuroendocrine mechanisms also participate in the inflammatory regulation caused by physical rehabilitation. Activation of the hypothalamic-pituitary-adrenal (HPA) axis during exercise increases the release of cortisol and catecholamines, hormones with recognized anti-inflammatory action, capable of inhibiting the production of cytokines such as TNF-α and IL-1β and reducing the migration of neutrophils and macrophages to peripheral tissues (Nieman; Wentz, 2019). In parallel, regular exercise induces improvement in cortisol sensitivity, preventing compensatory overproduction and reducing inflammation associated with chronic stress. This neuroimmunoendocrine effect contributes to breaking the cycle between stress, inflammation, and clinical worsening in patients with NCDs. Another decisive mechanism of physical rehabilitation involves the modulation of oxidative stress, an intrinsic component of chronic inflammation. Regular exercise increases the activity of endogenous antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, reducing the accumulation of reactive oxygen species (ROS) that activate inflammatory pathways such as NF-κB [14]. Sustained reduction in oxidative stress decreases inflammasome activation, limits cell damage, and improves mitochondrial functioning, creating a metabolic environment conducive to the reduction of proinflammatory cytokines. In this way, exercise becomes an essential therapeutic strategy in the restoration of cellular physiology.

Physical rehabilitation also has a relevant impact on the remodeling of adipose tissue, another critical point in the inflammation-metabolism axis. Regular physical activity reduces visceral fat mass and alters the phenotype of macrophages infiltrated in adipose tissue, promoting the transition from a proinflammatory profile M1 to an anti-inflammatory profile M2 [15]. This change decreases the production of TNF-α, IL-6, and MCP- 1, while also decreasing the production of TNF-. increases the secretion of diponectin, an adipocytokine with anti-inflammatory and insulin-sensitizing properties [4]. As a result, exercise disrupts one of the pillars of chronic inflammation, acting directly on the body’s largest reservoir of inflammatory cytokines. Finally, systemic adaptations promoted by exercise improve endothelial function, capillary expansion, increased cardiac output, increased muscle oxidative capacity, and autonomic regulation contribute to the overall reduction of the inflammatory state and physiological overload associated with chronic diseases [16]. These integrated effects explain why physical rehabilitation programs are considered core therapies in conditions such as cardiovascular disease, diabetes, COPD, and osteoarthritis. By modulating immunological, neuroendocrine, and metabolic pathways, therapeutic exercise is consolidated as an intervention of high clinical relevance in reducing low-grade systemic inflammation.

Impact of physical rehabilitation on inflammatory modulation in different chronic diseases

Physical rehabilitation applied to cardiovascular diseases has shown consistent results in the reduction of systemic inflammatory markers, especially C-reactive protein (CRP), IL-6 and TNF-α. Clinical studies show that structured aerobic exercise programs, even at moderate intensities, promote significant improvements in endothelial function and atherosclerotic plaque stability, mediated by the reduction of vascular inflammation [17]. This modulation occurs through mechanisms such as increasing nitric oxide, reducing oxidative stress, and changing the profile of macrophages infiltrated in the endothelium [18]. These findings justify the inclusion of physical rehabilitation as an essential part of the treatment of patients with coronary artery disease and heart failure. In the respiratory area, especially in individuals with chronic obstructive pulmonary disease (COPD), physical rehabilitation has a relevant impact on the reduction of systemic and local inflammation. Patients undergoing regular aerobic training and muscle strengthening programs show significant reductions in TNF-α, IL-8, and oxidative stress markers, as well as improved mitochondrial biogenesis and exercise tolerance [19]. The improvement of peripheral muscle function reduces the production of inflammatory metabolites derived from fatigued fibers, contributing to breaking the cycle between inflammation, dyspnea, and physical deconditioning [20]. Thus, respiratory rehabilitation not only improves ventilatory mechanisms, but also acts directly on immunometabolic processes.

In metabolic disorders such as type 2 diabetes mellitus and metabolic syndrome, physical rehabilitation promotes intense changes in the inflammation-metabolism axis, acting as a central intervention in reducing inflammation of low grade. Research shows that combined exercise (aerobic + resistance) significantly reduces baseline IL-6, ultrasensitive CRP, and TNF-α, while elevating IL-10, adiponectin, and improving insulin sensitivity [21]. In addition, exercise reduces the size of visceral adipocytes and decreases the infiltration of M1 macrophages into adipose tissue, promoting a more favorable anti-inflammatory microenvironment [15]. These effects explain the strong correlation between physical activity and improved clinical outcomes in metabolic diseases. In osteoarticular diseases, such as osteoarthritis and rheumatoid arthritis, physical rehabilitation reduces both systemic inflammation and intraarticular local inflammation. Supervised exercises, especially strengthening and low-impact exercises, reduce levels of IL-1β, TNF-α, and metalloproteinases in synovial fluid, in addition to decreasing cartilage degradation through modulation of the NF- κB pathway [22]. Meta-analysis studies also show significant improvement in pain, stiffness, and physical function, associated with reduced pro-inflammatory cytokines and increased antiinflammatory mediators [23]. These findings reinforce the essential role of rehabilitation as a non-pharmacological intervention for the management of osteoarticular diseases.

Finally, the effects of physical rehabilitation on inflammation also extend to systemic chronic diseases of a multifactorial nature, such as chronic kidney failure, autoimmune diseases, and agingrelated conditions. In renal patients, for example, intradialytic exercises reduce IL-6 and CRP, in addition to improving muscle strength and functional capacity [24]. In the elderly, regular exercise reduces inflammaging, lowering levels of IL-6 and TNF-α and improving immune function [25]. These cross-sectional effects show that physical rehabilitation acts broadly on inflammatory modulation, presenting benefits that go beyond the musculoskeletal system and reach multiple biological axes.

Clinical importance and gaps in the literature on physical rehabilitation and inflammatory markers

The clinical relevance of physical rehabilitation in the modulation of inflammatory markers is widely recognized, especially in the context of chronic non-communicable diseases, which represent one of the highest global morbidity and mortality burdens. The ability of therapeutic exercise to reduce proinflammatory cytokines, improve insulin sensitivity, optimize endothelial function, and promote immunometabolic balance makes this intervention a strategic tool for the management of conditions such as diabetes, heart failure, COPD, and osteoarthritis [5]. Although the role of exercise in functional improvement is already consolidated, recent advances show that its molecular impact is equally determinant for the control of the progression of NCDs, reinforcing their relevance for individualized clinical protocols [13]. Despite progress in understanding exerciseinduced anti-inflammatory mechanisms, important gaps related to the heterogeneity of individual responses still persist. Genetic variations, differences in baseline inflammation level, body composition, age, sex, gut microbiota, and the presence of multiple comorbidities influence the magnitude of the inflammatory response to exercise [26]. This diversity highlights the need to develop personalized approaches, considering that some patients exhibit robust anti-inflammatory responses, while others exhibit more discreet or even inconsistent responses, despite similar protocols. Thus, understanding predisposing factors can optimize interventions and improve therapeutic efficacy.

Another relevant gap refers to the standardization of physical rehabilitation protocols used in clinical studies. There is great variability in the intensity, duration, frequency, and type of exercise among the studies, which makes it difficult to compare the results and limits the construction of robust evidence-based guidelines [27]. In addition, many studies use small sample sizes, short intervention periods, and assessments limited to a few inflammatory markers, reducing the ability to extrapolate conclusions to larger populations. The absence of methodological standardization remains one of the main challenges in the consolidation of universal clinical recommendations. There is also a lack of studies addressing the long-term effects of physical rehabilitation on inflammatory modulation, especially in patients with multiple comorbidities, frail older adults, and populations of high clinical complexity. Most research focuses on 8- to 12-week interventions, leaving gaps on the sustainability of anti-inflammatory effects, the persistence of immunometabolic adaptations, and the cumulative impact of exercise over years [25]. Understanding long-term effects is essential to determine whether physical rehabilitation can act as a disease-modifying strategy and not just as an adjunctive intervention.

Finally, despite the growing number of studies, there are still few studies that integrate multiple biological dimensions such as inflammation, mitochondrial function, adipose tissue composition, gut microbiota, and neuroendocrine axes into a single analysis model. The literature tends to study inflammatory markers in isolation, which limits the systemic understanding of the effects of exercise and prevents the construction of integrated pathophysiological models [1]. Thus, the main gap in the area lies in the need for multidimensional, multicentric and longitudinally robust, capable of capturing the complexity of the interactions between exercise, metabolism, and inflammation. Studies of this type would allow the consolidation of exercise as a first-line therapeutic intervention in the management of chronic inflammation.

Role of physical rehabilitation and the role of physical therapists in inflammatory modulation

The role of the physical therapist plays a central role in the prescription, monitoring and therapeutic modulation of physical interventions aimed at reducing systemic inflammation in patients with chronic diseases. While physical exercise can be conducted by different professionals, the physical therapist has specific training in biomechanics, clinical exercise physiology, kinesiology, pathophysiology and rehabilitation, allowing the construction of individualized protocols based on the functional and inflammatory status of each patient [28]. This differential allows the physiotherapist to adapt loads, intensities, volumes, and stimuli safely, preventing joint overloads, adverse events, and exacerbated inflammatory responses. Thus, its action becomes decisive for patients with NCDs, who are often frail, polymedicated, or have significant functional limitations.

Physical rehabilitation guided by the physiotherapist integrates various modalities, such as aerobic exercise, resistance training, therapeutic stretching, functional training, manual techniques and cardiorespiratory approaches, all with evidence of modulation of inflammatory markers. The physiotherapist structures these interventions based on careful assessments, such as submaximal cardiorespiratory tests, dynamometry, functional scales, and muscle performance measures, allowing dynamic adjustments according to clinical evolution [29]. This ability to measure therapeutic response ensures progressive interventions, avoiding insufficient or excessive stimuli, both associated with worse immune responses. In this way, physiotherapy acts not only in functional rehabilitation, but as a biological strategy to control inflammation. Resistance training, when prescribed by physiotherapists, has significant impacts on muscle metabolism and on the release of anti-inflammatory myokines. Studies show that supervised strengthening increases IL-10 production and reduces circulating TNF-α, in addition to improving muscle structural parameters and reducing inflammatory sarcopenia, which is frequent in the elderly and patients with chronic diseases [30]. Physiotherapeutic supervision ensures correct execution, appropriate load selection, speed control and injury prevention, fundamental aspects to achieve anti-inflammatory responses without generating mechanical stress excessive. Thus, resistance training under physical therapy conduction produces combined functional, metabolic and immunological benefits.

Aerobic exercise also stands out in physical therapy practice for its strong association with the reduction of low-grade systemic inflammation. Supervised aerobic programs reduce CRP, IL-6, and oxidative stress markers, in addition to increasing cardiorespiratory capacities that are fundamental for the management of cardiovascular, metabolic, and respiratory diseases [31]. The physiotherapist adapts intensity and monitors heart rate, peripheral oxygen saturation, ventilation, subjective perception of exertion, and clinical response, ensuring safety especially for at-risk populations, such as cardiac patients, diabetics, and patients with pulmonary limitations. Aerobic intervention, therefore, becomes more effective and safer when integrated with clinical physical therapy reasoning.

In addition to exercise modalities, manual techniques and respiratory therapies applied by the physiotherapist also have indirect effects on inflammation, by improving joint mobility, reducing pain, optimizing ventilation, reducing bronchospasm and favoring global functionality. Studies reveal that chest physiotherapy reduces pro-inflammatory cytokines in COPD patients, while manual interventions reduce inflammatory mediators in chronic musculoskeletal conditions [32]. The integration of these practices with structured exercise keeps the physiotherapist in a strategic position to address chronic inflammation from multiple therapeutic axes. Thus, physical rehabilitation becomes a field in which physical therapy acts as a protagonist in the immunometabolic modulation of chronic diseases.

Relevance and possible impacts of the review for the areas of Biomedicine, Public Health and Physiotherapy

The integration between Biomedicine, Public Health, and Physical Therapy is fundamental to understand the complexity of chronic inflammation and its interfaces with the biological, functional, and social determinants of health. In the field of Biomedicine, this review offers essential elements to deepen the understanding of molecular and immunometabolic pathways modulated by exercise, including the action of myokines, adipokines, inflammatory cytokines, and oxidative stress markers, allowing biomedical professionals to act both in diagnosis and in clinical monitoring based on biomarkers [2]. The systematization of these mechanisms expands the translational potential of laboratory research for clinical practices, strengthening the role of Biomedicine in the management of complex inflammatory and metabolic diseases. From a Public Health perspective, the results of this review highlight exercise and physical rehabilitation as low-cost strategic tools, high effectiveness and population impact, which are fundamental for coping with chronic non-communicable diseases (NCDs), which remain the main causes of global morbidity and mortality. Interventions based on supervised physical activity reduce systemic inflammatory burden, improve functional capacity, reduce hospitalizations, and increase the autonomy of individuals, which is in line with international guidelines for health promotion and disease prevention [33]. Thus, this review reinforces the need for public policies that include physical rehabilitation as a structuring component of primary care and health surveillance.

In Physical Therapy, the findings reinforce the centrality of the physical therapist in inflammatory modulation through individualized, evidence-based interventions based on clinical reasoning. The synthesis presented in this review legitimizes professional performance in protocols that combine aerobic exercise, resistance training, manual therapies, and cardiorespiratory interventions, demonstrating that such practices directly influence immunological, metabolic, and functional pathways [16]. In addition, the review offers subsidies for the qualification of clinical practice, curricular improvement and expansion of applied research, strengthening the role of Physical Therapy in coping with NCDs. Thus, the impact of this review is manifested in a transversal way, contributing to multiprofessional integration and scientific advancement in the three areas.