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Pathology, Inflammation
Introduction
Inflammation is an ancient medical term initially referring to classic signs and symptoms, including edema, erythema (redness), warmness, pain, and loss of function (stiffness and immobility).[1] Currently, inflammation is recognized as a set of changing responses to tissue injury primarily caused by factors such as toxic chemicals, environmental agents, trauma, overuse, or infection. Some of these responses can facilitate wound healing and infection control or pathology, as in many chronic disease states.[2] Inflammation is a second-line defense against infectious agents. The responses evoked by inflammation are a keystone of pathology. Diseases where inflammation plays a dominant pathological role have the suffix -itis. Both cell-mediated and humoral responses of the immune system are central to inflammation.[3] This activity summarizes how inflammation is linked to cardiovascular disease and cancer, two global causes of mortality and morbidity.
Issues of Concern
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Issues of Concern
Acute or Chronic Inflammation
Acute inflammation has a rapid onset of minutes or hours, typically resolves within a few days, has classic signs and symptoms, and has a cellular infiltrate primarily consisting of neutrophils.[4] The erythema observed in acute inflammation results from increased blood flow to the affected area due to vasodilation. Vasodilation is triggered by various mediators, with histamine as a notable example, acting on vascular smooth muscle. This process initially affects the arterioles and opens new capillary beds in the affected area.[5] Besides blood vessels, lymphatic vessels are active in acute inflammation. In inflammation, lymph flow is increased and helps drain edema fluid that accumulates because of increased vascular permeability. Along with fluid, leukocytes, cell debris, and microbes may also enter the lymph.[6] Similar to blood vessels, lymphatic vessels proliferate during inflammatory reactions to handle the increased load.[7]
The acute inflammatory process is a 4-stage process that begins with the initiation phase, triggered by the injury. This phase involves changes to the microcirculation, leading to fluid loss and the migration of white blood cells to the injured area. The amplification phase follows, where chemical substances direct additional types of white blood cells to the site, enhancing the response. The rapid neutralization of the injury and debris removal characterizes the destruction phase. Finally, the termination phase requires the action of chemical substances to halt or regulate the inflammatory process, preventing excessive damage if unchecked.[2]
Cryotherapy is an effective treatment for acute inflammation caused by musculoskeletal injury, leading to decreased pain and more rapid return to participation. [8] The primary mechanism is reduced sensory nerve transmission at the site, whereas peripheral vasoconstriction slows the metabolic rate. Reducing oxidative stress reduces secondary ischemic injury and alleviates inflammation.[9] Cryotherapy is most effective when applied soon after the injury, within 24 to 48 hours.[10] Chronic inflammation has a slow onset of days, a long duration of years, less prominent classical signs and symptoms, and cellular infiltrate composed of monocytes, macrophages, and lymphocytes.[11] Chronic inflammation can arise from persistent infections caused by microorganisms that are difficult to eliminate, such as mycobacteria, viruses, fungi, and parasites, triggering delayed-type hypersensitivity reactions that may lead to granulomatous responses or unresolved acute inflammation evolving into a chronic state.[12]
Prolonged exposure to toxic agents, whether exogenous, such as particulate silica causing silicosis, or endogenous, such as excessive cholesterol and lipids contributing to atherosclerosis, can also induce chronic inflammation.[13] In addition, chronic inflammation occurs in diseases not typically viewed as inflammatory disorders, including neurodegenerative diseases such as Alzheimer disease, metabolic syndrome, type 2 diabetes, and certain cancers, where inflammatory processes promote tumor development.[14][15]
Mediators and Biomarkers of Inflammation
The discovery of cellular and molecular inflammatory mediators and the development of sensitive biomarkers have rapidly advanced our understanding of inflammation and its role in pathology.
Key biomarkers include:
- Reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS)
- Formation of DNA adducts
- Cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha, and chemokines
- Acute-phase proteins, such as C-reactive protein or CRP
- Prostaglandins
- Cyclooxygenase (COX)-related metabolites
- Inflammation-related growth factors and transcription factors, such as NF-kappaB
- Major immune cell types
The specific immune cells and mediators at play are variable and dependent upon the injury, the onset or duration of the injury, and multiple genetic loci. CRP is a widely used clinical inflammatory biomarker that presents in 2 forms with distinct functions—a homopentamer termed native CRP and a monomer. Two clinical assays are available for CRP—a standard assay and a high-sensitivity assay (hs-CRP).[1][16][17][18][19]
Inflammation and Cardiovascular Disease
Hs-CRP is often used to evaluate increased cardiovascular disease risk. Increased levels of plasma hs-CRP are a cardiovascular risk factor, in addition to low-density lipoprotein cholesterol and the degree of metabolic syndrome. Some suggest that increased inflammation from any cause, such as periodontal disease and arthritis, damages vascular endothelium. Central obesity, a risk factor for type 2 diabetes and cardiovascular disease, is also associated with increased hs-CRP in metabolic syndrome. However, it remains uncertain whether CRP plays an active role in causing heart disease or if lowering hs-CRP is a valid goal for preventing heart disease.[20][21]
In contrast, the 2018 CANTOS trial on tertiary prevention in patients with a history of myocardial infarction demonstrated that reducing hs-CRP levels with canakinumab effectively decreased major cardiovascular events by 25%. This effect was primarily observed in patients whose treatment lowered hs-CRP levels to less than 2 mg/mL. Canakinumab is a monoclonal antibody that targets interleukin-1-β and does not affect plasma lipoprotein levels. Most participants in the CANTOS trial were already on statin therapy.[22] Statins, besides lowering low-density lipoprotein cholesterol, also lower hs-CRP. Nevertheless, a large-scale study found that simvastatin's effectiveness in lowering a first major vascular event was unaffected by baseline CRP levels.[23]
Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic, antipyretic, antiplatelet, and anti-inflammatory effects.[24] These drugs are among the world's most used or prescribed medications. The effects of NSAIDs on CRP levels are mixed and depend upon the particular NSAID.[25] In patients taking NSAIDs for rheumatoid arthritis, naproxen was associated with a decreased CRP, whereas lumiracoxib was associated with an increased CRP.[26] Lumiracoxib is a selective inhibitor of COX-2, the inducible form of COX, whereas naproxen is a nonselective COX inhibitor, inhibiting COX-2 and COX-1, the constitutively expressed form of COX. The COX-2 selective inhibitors are collectively called coxibs. The more selective an NSAID is for COX-2, the greater the effect on increasing CRP. Due to the increased risk of severe cardiovascular events, celecoxib is the only coxib available in the American market.[27] The cardiovascular risks posed by NSAIDs are an area of active research and are an under-recognized issue.
Inflammation, Aging, and Cancer
Inflammation is closely associated with an increased production of ROS and RNOS, which can damage DNA. Chronic inflammation is a process that can increase mutations and cancer risk. Increased cellular or tumor microenvironmental ROS production is associated with diminished control of cell growth. For example, activated macrophages are a major source of ROS, and these inflammatory cells are located in the tumor microenvironment of breast cancer tumors, promoting growth and metastasis. Chronic inflammation is associated with many types of cancer and all stages of cancer.[28]
Obesity, which increases chronic inflammation, is now recognized as a major and preventable increased cancer risk factor. Increasing evidence supports a strong positive association between CRP levels and cancer. For example, elevated CRP levels at the time of diagnosis are associated with breast cancer, its subtypes, and poor outcomes.[29] Elevated levels of CRP are all positively associated with the risk of epithelial cancers, such as liver, lung, colorectal, endometrial, breast, and ovarian cancer. CRP levels are a valuable prognostic biomarker in various adult tumors. Elevated CRP levels are linked with a shorter survival time for most solid tumors.[30] Aging is a major risk factor for cancer, and systemic, sterile (non-infection-caused), age-related chronic inflammation—termed inflamm-aging or inflammaging—is an underlying etiological connection.[31] CRP and other inflammatory biomarkers increase with age. Gut microbiota is more pro-inflammatory with aging and contributes to systemic chronic inflammation.[32]
Diet, Exercise, and Inflammation Levels
Over the last decade, a relatively consistent understanding of the relationship between lifestyle and inflammation has emerged. Individuals with high CRP levels of greater than 3.0 mg/L tend to be physically inactive, have higher plasma glucose levels, are less likely to follow the Mediterranean diet, have a higher incidence of hypertension, have a lower HDL-cholesterol (anti-atherogenic), and increased abdominal obesity. Adopting a Mediterranean diet combined with a medium physical activity markedly reduces the incidence of high CRP by 72%. The dietary inflammatory index is a flexible tool for accessing the relationship between diet and inflammation, with smartphone apps available for easy access.[33]
Clinical Pathology
Specimen collection and processing are crucial for avoiding common preanalytical errors and ensuring accurate test results. Confirming the patient's identity is the most important step in phlebotomy, ensuring that the collected specimen is from the correct patient and is matched to the correct test request form. For hs-CRP testing, serum is typically the preferred specimen type. However, other acceptable options include lithium, heparin plasma, K2-EDTA plasma, and whole blood, especially capillary whole blood obtained through a fingertip prick. The median cubital vein in the antecubital fossa is the preferred site for collecting venous blood in adults because the vein is large and is close to the skin's surface.[34][35][34][36]
Particle-enhanced turbidimetry and nephelometry are 2 common techniques used for hs-CRP quantitative determination in clinical laboratory settings. Both methods rely on the principle of light scattering by antigen-antibody complexes but differ slightly in the geometry of light detection. In both techniques, monoclonal or polyclonal antibodies specific to hs-CRP are immobilized (adsorbed) onto the surface of latex particles. These particles are typically made of polystyrene and have a uniform size. When a sample containing hs-CRP is introduced, the antigen (hs-CRP) binds to the specific antibodies on the latex particles, forming antigen-antibody complexes.[37][38]
Turbidity measures the total amount of light scattered by a solution at an angle of 180° from the incident light source, similar to the absorbance measurements in a spectrophotometer. The key concern of turbidimetric measurements is a signal-to-noise ratio, which is critical for accurate measurements at low concentrations. The nephelometer measures the light scattered by the antigen-antibody complexes at a right angle (90°) to the incident light source. This specific angle provides a stronger signal for the antigen-antibody complexes compared to the background light scattering from the solution. Using latex particles with immobilized antibodies enhances the sensitivity of the measurement, especially at low hs-CRP concentrations, which is important for assessing low-grade inflammation. These techniques are readily automated and can be integrated into clinical chemistry analyzers, allowing for high-throughput analysis of hs-CRP levels.[39][40][41]
Clinical Significance
The signs of inflammation include loss of function, heat, pain, redness, and swelling. Inflammation is part of the body's biological response to harmful stimuli, such as irritants, pathogens, and damaged cells. Differentiating inflammation and infection is clinically relevant due to many pathologies that distinguish evaluation and treatment.
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