General Pathology Series: Acute vs. Chronic Inflammation
Foreword
Inflammation is a vital reaction mechanism to threats, and it is part of a beneficial defense system that has evolved and been conserved evolutionarily over thousands of years. But why is this process associated with diseases? While inflammation is primarily protective and helps maintain tissue equilibrium, uncontrolled inflammation can become detrimental, leading to the progression of chronic inflammatory diseases. This series aims to provide a comprehensive understanding of the inflammatory process by emphasizing its historical context, intricate mechanisms, and events that will determine its end or the development of diseases. Through six captivating chapters, readers will obtain a holistic perspective on inflammation and its significance in health and disease.
This series is divided into six articles including:
General Pathology Series: Inflammation - Historical Perspectives
General Pathology Series: Inflammatory Cells Recruitment and Clearance
General Pathology Series: Acute vs. Chronic Inflammation
General Pathology Series: Acute vs. Chronic Inflammation
In simple terms, acute inflammation is a short-term response that occurs rapidly after tissue injury or infection, while chronic inflammation is a long-term response that can persist for months or years. But what determines whether an inflammatory process will be acute or chronic? Several factors can be decisive in the development of short-term inflammation that culminates with resolution or long-term inflammation, where the resolution process fails. Factors such as the intensity of the response, exposure to the harmful agent, and genetic and environmental factors are decisive in predicting whether an inflammation will be acute or chronic. The following sections will be focused on both describing the main acute and chronic inflammation features and discussing the existing evidences on preventive measures for the chronic diseases development.
General Concepts
Inflammation is part of a beneficial defense system that maintains tissue equilibrium, but if uncontrolled it can become deleterious, progressing to a chronic state (Panezai & Van Dyke, 2022). An acute inflammatory response is typically a self-limiting, rapid, and short-term process, usually lasting a few days to a few weeks when the resolution and tissue repair occur [Figure 1]. It is usually triggered by a harmful stimulus such as infection or tissue injury. Acute inflammation involves the rapid recruitment of immune cells (such as neutrophils) from the bloodstream to the site of injury or infection, a mechanism mediated by the release of inflammatory molecules. These mediators induce blood vessel dilation to increase blood flow and permeability, allowing immune cells to reach the affected area. These events contribute to the development of the classic signs of inflammation, known as cardinal signs of inflammation, comprising rubor (redness), calor (fever), tumor (swelling), dolor (pain), and functio laesa (loss of function) (Medzhitov, 2010).
However, the main characteristics of acute inflammation as the appearance of the classic cardinal signs, may not be experienced with chronic inflammation. Chronic inflammation is a low-grade persistent inflammation that can last for months, or even years. It is a state where the resolution of the inflammation process fails or when the inflammatory response is exacerbated, often associated with the body’s inability to eliminate the threat (Medzhitov, 2010). The chronic inflammatory state can result from persistent infections, exposure to irritants (such as prolonged exposure to smoke or certain chemicals), autoimmune diseases, or chronic inflammation may be driven by stimuli that are persistent and cannot be effectively cleared, such as in the case of silicosis.
Unlike acute inflammation, in which the majority of cells recruited to the injured tissue are neutrophils, chronic inflammation involves a more diverse set of immune cells, comprising the activation and accumulation of lymphocytes and macrophages into tissues (Pahwa et al., 2023). Chronic inflammation is in nature generally systemic, meaning it can affect every organ and tissue in the body, including the skin, liver, lungs, kidneys, brain, etc. Furthermore, it is persistent, which even makes it harmful (Vasto et al., 2007). This type of inflammation can be triggered by external sources—viral or bacterial infections, allergens or toxins from the environment, smoking, and alcohol consumption—or it can also be triggered by internal states including stress, metabolites, autoantibodies, and genetic susceptibility. The prolonged inflammation characteristic of chronic inflammation [Figure 2] can induce tissue damage and it is associated with various chronic diseases, including arthritis, cardiovascular diseases, and cancer (Furman et al., 2019).
A hallmark of chronic inflammation is that tissue destruction and repair can occur simultaneously, leading to the formation of granulomas or tissue fibrosis (scar tissue). Granulomatous inflammation is characterized by the presence of granulomas formed by the aggregation of activated macrophages or its derived cells called epithelioid cells usually surrounded by lymphocytes [Figure 3]. The macrophages or epithelioid cells often coalesce to form Langhans cells—multinucleated giant cells (Shah et al., 2017). Fibrosis denotes excessive scarring, which exceeds the normal wound healing response. It is characterized by the accumulation of fibrous connective tissue, which replaces the functional cells of a certain organ. Organ fibrosis in response to chronic tissue injury may disintegrate the regular architecture of the organ and subsequently promote organ failure. This is well known, for example, in chronic liver diseases, where conditions such as cirrhosis, reach an irreversible end-stage with impaired organ function (Weiskirchen et al., 2019).
Symptoms of Chronic Inflammation
While acute inflammation is marked by the classic cardinal signs of inflammation such as redness, heat, swelling, and pain, the common signs and symptoms developed during chronic inflammation [Figure 4] can vary (Pahwa et al., 2023). The main symptoms associated with chronic inflammation are listed below:
Body pain - arthralgia (joint pain), myalgia (muscle pain)
Persistent fatigue and insomnia
Mood disorders - depression, anxiety
Gastrointestinal complications - constipation, diarrhoea, and acid reflux
Weight gain or weight loss
Frequent infections
Risk Factors Associated with Chronic Inflammation
There is plenty of evidence suggesting that chronic inflammation can precede several chronic diseases. Chronic diseases are the leading causes of death and disability worldwide—about 70% of all deaths in the population are associated with these conditions (World Health Organization [WHO] 2022). Some risk factors linked to chronic inflammation, and consequently responsible for the chronic diseases arise [Figure 5] will be furhter discussed.
Aging: Several studies have shown that increasing age is positively correlated with higher levels of several inflammatory molecules. The low-grade persistent inflammation state associated with aging is called inflammaging. The inflammatory state that comes with aging results mainly from the generation of free radicals and other harmful molecules that promote cell damage and organ deterioration (Kirkwood & Kowald, 2012). In inflammaging, mechanisms of tissue repair and maintenance that constantly occur in the body are compromised, leading to the accumulation of injured cells. The accumulation of injured cells increases the production of pro-inflammatory molecules, maintaining their persistent levels in body tissues. Another aspect of inflammaging is the accumulation of senescent cells, which are “old cells” that are no longer able to divide and promote tissue regeneration, contributing to a tissue proinflammatory state (Sanada et al., 2018). This low-grade chronic inflammation that comes with age will contribute to the development and progression of chronic or degenerative diseases [Figure 6], including obesity, cardiovascular ones, cancer, depression, dementia, osteoporosis (bone loss), and sarcopenia (muscle mass loss) (Ferrucci & Fabbri, 2018).
Poor diet: It is already known that specific diets can modulate inflammation. Careful selection of foods of an anti-inflammatory nature [Figure 7], and avoiding a pro-inflammatory diet, are essential for disease prevention and the maintenance of a healthy state. An anti-inflammatory diet plan consists of a pattern of eating that focuses on consuming whole, plant-based foods that are rich in healthy fats and phytonutrients. This measure can prevent cellular stresses, promote healthy gut microbiota, and inhibit pro-inflammatory signaling due to the presence of antioxidant and anti-inflammatory molecules. A diet rich in saturated fat, trans-fats, and refined grains, and sugar is associated with higher production of pro-inflammatory molecules, leading to a greater tendency to develop diseases, especially metabolic and cardiovascular disorders (Stromsnes et al., 2021).
Physical inactivity: Fighting a sedentary lifestyle can be considered a public health challenge of the 21st century. There is substantial evidence that regular physical activity has important and wide-ranging health benefits. On the other hand, physical inactivity increases the risk of the development of several chronic diseases cardiovascular and metabolic nature, including diabetes, obesity, hypertension, and atherosclerosis, among others. Lack of physical activity leads to chronic inflammation induced by the accumulation of visceral fat and is commonly accompanied by fatigue and muscle wasting. Deconditioned muscles and exacerbated inflammation, along with other comorbidities and disease-specific symptoms, negatively affect cardiovascular performance and the ability to perform physical activity, closing the vicious cycle of a sedentary lifestyle and unhealthy lifestyle (Burini et al., 2020).
Obesity: An increase in adipose tissue (fat tissue) is a hallmark of obesity. Many studies have reported that fat tissue is an endocrine organ (that produces hormones) secreting multiple molecules. A growing body of evidence supports the claim that increased adipose tissue mass directly correlates to systemic inflammation (Wu & Ballantyne, 2020). Adipose tissue can release pro-inflammatory factors, contributing to the development of chronic diseases such as diabetes, heart disease, and osteoarthritis (Berg & Scherer, 2005).
Smoking: Cigarette smoke does promote chronic inflammation and tissue damage in the conducting airways [Figure 8] as it contains several toxins and traces of microbial cell components that can trigger the immune system. These compounds can induce chronic inflammation in the mucosal surfaces, like the oral cavity and lungs as well as systemic inflammation, leading to the development of cancer, chronic lung and vascular diseases, and oral disorders (Lee et al., 2012).
Stress and sleep disorders: Stress can trigger the release of stress hormones like cortisol and adrenaline, preparing the body to respond to a perceived danger or stressful situation—a fight-or-flight response. Cortisol also has anti-inflammatory properties. However, prolonged exposure to high cortisol levels during stress can suppress its normal functions: while cortisol initially helps suppress inflammation, persistent cortisol level elevation can lead to a feedback loop where the body becomes less responsive to cortisol's anti-inflammatory effect. In addition, stress is also associated with inflammatory cytokine release (Slavich & Irwin, 2014). Stress can also cause sleep disturbances. Individuals with irregular sleep schedules are more likely to have chronic inflammation than people with consistent sleep (Ditmer et al., 2021). Therefore, sleep disorders are also considered risk factors for chronic inflammation.
Chronic Inflammation and the Development of Non-communicable Diseases
Non-communicable diseases (NCDs) are diseases that are not spread through infection or other people (non-transmissible) but are typically caused by unhealthy behaviors. NCDs are also known as chronic diseases and are characterized by a non-contagious nature, multiple lifestyle-associated risk factors, a long latency period, and incurability (Piovani et al., 2022). These conditions are responsible for more than 41 million deaths every year, a number that represents more than 70% of all deaths worldwide. Furthermore, millions of people live with NCDs and have a reduced quality of life. The main types of NCDs [Figure 9] are cardiovascular diseases—the most prevalent, including heart disease and stroke (representing 17.9 million deaths per year), cancer (9.3 million deaths per year), chronic respiratory diseases—including chronic obstructive pulmonary disease and bronchial asthma (4.1 million deaths per year), and diabetes mellitus (2 million deaths per year) (WHO, 2023). The list of NCDs also includes neurological and mental health diseases (e.g., Alzheimer's disease, Parkinson's disease, depressive disorders, schizophrenia, and dementia), digestive diseases (e.g., peptic ulcers, inflammatory bowel diseases, and liver cirrhosis), joint and musculoskeletal diseases (e.g., osteoarthritis, rheumatoid arthritis, osteoporosis, sarcopenia, and gout), chronic kidney disease, autoimmune diseases, and others (Piovani et al., 2022). Although the development of these diseases can be triggered by different agents, increasing evidence suggests that inflammatory processes underlie most NCDs (Camps & Garcia-Heredia, 2014; Furman et al., 2019; Nediani & Dinu, 2022).
Of all 41 million deaths occurring globally each year, one-quarter occur in high-income countries while approximately three-quarters occur in low- and middle-income countries. Furthermore, around 17 million people die from NCDs each year before reaching 70 years of age, with the majority (86%) of these premature deaths occurring in low- and middle-income countries (Piovani et al., 2022). These data highlight that the poorest countries, disadvantaged societies, and least-favoured people of each nation at large, are more susceptible to the development of those conditions due to the “westernization of lifestyle”, with increased stress, unhealthy diets, and a sedentary lifestyle. The fact is that most of the morbidity and mortality from NCDs could be avoided or delayed, and millions of people could live longer and healthier (WHO, 2022). Factors that may increase the risk of developing NCDs can be classified as non-modifiable (e.g., age, sex, genetic factors, and ethnicity), or modifiable (which entails lifestyle changes such as diet, stress modulation, and incorporation of regular physical activity) (Piovani et al., 2022).
Ways to Prevent Chronic Inflammation: Influence of Lifestyle
Most of the research involving chronic diseases has focused on discovering targets for treating these conditions. In contrast, less research has focused on what causes or exacerbates the severity of these diseases. The mechanisms and causative agents that initiate the chronic response of certain chronic diseases (e.g. Systemic Lupus Erythematosus) are often not identified clearly. However, even though many chronic diseases cannot be cured, they can be treated and, more importantly, prevented. A number of lifestyle modifications have proven to be effective in reducing chronic inflammation severity and reversing its progression. Lifestyle changes—including incorporating regular exercise, managing weight effectively, maintaining a balanced diet, ensuring sufficient quality sleep, reducing stress levels, and abstaining from tobacco and alcohol consumption—have been shown to play a crucial role in reducing a body’s pro-inflammatory state.
For a person who has maintained healthy habits throughout their life, the chances of developing chronic diseases are less probable. A healthy lifestyle can help to circumvent a proinflammatory state in someone’s body. For example, studies have shown that exposure to environmental factors, such as a poor dietary pattern is associated with changes in the bacterial composition of the gut (O'Toole & Jeffery, 2015). Changes in the gut microbial composition have been associated with an imbalance of the normal microbial community (dysbiosis) with the prevalence of pathogenic species in the gut, which can increase systemic levels of inflammatory mediators. A diet rich in fiber is involved in generating short-chain fatty acids, molecules that facilitate the growth of beneficial bacteria in the gut while inhibiting the growth of pathogenic bacteria. This, in turn, helps reduce the production of inflammatory mediators, thus promoting a healthier intestinal environment and reducing the chances of developing chronic diseases (Figure 10). Several other nutritional compounds can also help in preventing chronic inflammation. These molecules, found mainly in fruits and vegetables, display antioxidant and anti-inflammatory properties. Some examples are phenolic compounds, terpenes/terpenoids, and ômega-3 (an important precursor of pro-resolving mediators) (Sansbury & Spite, 2016).
Engaging in regular physical activity to maintain an optimum weight plays a pivotal role in preventing or mitigating a highly prevalent chronic condition of our time: obesity. The current lifestyle, with low physical activity and a poor diet low in nutrients, favors the accumulation of fat tissue, as well as the development of insulin resistance (Ahima, 2009). Insulin resistance refers to a diminished ability of cells to take up glucose from the bloodstream, consequently disrupting blood sugar levels and contributing to the development of obesity-related diseases like diabetes. Elevated levels of glucose and free fatty acids (elevated in most obese individuals especially due to a poor diet) induce the production of inflammatory molecules and increase the risk of developing other chronic diseases such as cardiovascular diseases (Ellulu et al., 2017). The combination of regular exercise and a healthy diet can strengthen the heart, muscles, and bones, decreasing the risk of chronic disease manifestation.
Lower stress levels associated with adequate sleep practices can also reduce the development of a chronic inflammatory condition (Slavich & Irwin, 2014). Overnight sleep increases the production of growth hormones, which play a crucial role in tissue renewal and repair. Furthermore, chronic psychological stress has been linked to a greater risk of depression, heart disease, and the body's general dysfunction, weakening the defense system and increasing the individual's susceptibility to infections (Ditmer et al., 2021). Together, these factors regulate the body’s inflammation by reducing the release of free radicals and inflammatory mediators, consequently increasing tissue repair, modulating metabolism, and improving overall quality of life and well-being.
Chronic diseases are the greatest global public health challenge of the 21st century. The adoption of prevention strategies for chronic inflammatory diseases, including NCDs, is considered the most cost-effective, accessible, and sustainable measure to address the burden of these conditions worldwide. Indeed, the costs associated with medical care for those already affected represent a great burden. Global prevention and control strategies for these conditions should aim to reduce the incidence of NCDs, delay the onset of disease and disability, alleviate disease severity, and improve health-related quality and the length of life of individuals. Health promotion activities such as raising awareness, encouraging healthy lifestyles; addressing modifiable risk factors; early detection programs, i.e. screening of populations at high risk of developing chronic diseases; and initiatives aimed at managing NCDs and the complications associated, can play a fundamental role in controlling chronic diseases globally (Piovani et al., 2022).
Conclusions
Inflammation is part of a beneficial defense system against threats and it is prompted and activated in response to tissue damage and involves several cells and molecules. While acute inflammation is self-limiting and progresses to an end, chronic inflammation is persistent, culminating in the development of chronic diseases. Acute and chronic inflammation can be distinguished in relation to the intensity of the response, cellular components, associated symptoms, and risk factors. While acute inflammation is an intense and immediate response, chronic inflammation is low-intensity and persistent. An inflammatory response where the mechanisms of resolution fail can become chronic.
Chronic inflammatory diseases affect millions of people and are the most prevalent diseases around the world, displaying substantial mortality rates. These conditions represent one of the biggest public health problems of the 21st century. Despite advances related to the mechanisms behind the development of chronic diseases, as well as the discovery of pharmacological targets and improvements in therapy, measures to prevent these diseases are still one of the best practices to be adopted. Inflammatory processes are very complex, and chronic inflammatory diseases are treatable but not cured. Studies in this area still need to be further explored.
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