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Pathophysiology of oral cavity diseases. Textbook
A. Yu. Ryabinina
M. L. Blagonravov
A. A. Bryk
This textbook is intended for students of medical universities specializing in «Dentistry», as well as for residents and postgraduate students. It has been prepared by authors from the Medical Institute of the Federal State Autonomous Educational Institution of Higher Education «Peoples’ Friendship University of Russia named after Patrice Lumumba». The textbook presents relevant educational material on the pathogenesis of dental diseases.

Pathophysiology of oral cavity diseases
Textbook

A. A. Bryk
A. Yu. Ryabinina
M. L. Blagonravov

© A. A. Bryk, 2024
© A. Yu. Ryabinina, 2024
© M. L. Blagonravov, 2024

ISBN 978-5-0064-8007-0
Created with Ridero smart publishing system

INTRODUCTION
The textbook comprehensively addresses pathophysiology of dental diseases, covering the pathogenetic basis of inflammatory processes, the role of microflora, mechanisms of immunity, characteristics of dystrophic changes, as well as microcirculatory and functional disorders of the oral cavity. Special attention is given to the pathogenesis of inflammatory diseases such as pulpitis, periodontitis, gingivitis, and others. Additionally, the influence of systemic diseases on the condition of oral cavity tissues is discussed.
The purpose of this textbook is to provide students with contemporary educational material on the pathogenesis of various dental diseases in an accessible format, as well as to assist in the development of professional skills necessary for successful practical activity.

FEATURES OF NON-SPECIFIC PATHOLOGICAL REACTIONS IN THE ORAL CAVITY

Despite the variety of pathological conditions in the oral cavity, several key pathogenetic mechanisms that underlie the development of dental diseases of various etiologies can be identified. The typical (non-specific) pathological reactions affecting oral tissues include:
– Inflammation
– Dystrophy (including against the background of microcirculatory disturbances)
– Functional (hyperfunction) and mechanical trauma
– Functional insufficiency (hypofunction)
– Tumor growth (neoplasia)
These typical processes have several key characteristics. The pathogenesis of inflammation in the oral cavity is primarily influenced by microflora. In case of dystrophic changes in the periodontium, degenerative alterations predominate with no signs of the inflammatory process. Functional disorders are caused by prolonged hypo- or hyperfunction of periodontal tissues. Mechanical damage to tooth tissues can include, for example, improper use of hygiene products – horizontal movements with a toothbrush that contribute to the formation of non-carious lesions, and the use of hard-bristled toothbrushes leading to gingival recession, including the loss of marginal gingiva and exposure of the tooth root, as well as iatrogenic factors that exert a traumatic impact on periodontal tissues (such as overhanging edges of fillings and crowns, or poor-quality filling of the contact surfaces of teeth leading to trauma to marginal areas of the periodontium). The development of neoplastic processes is associated primarily with disruptions in the growth and differentiation of cells within oral tissues.

INFLAMMATION

Inflammation is a non-specific response to injury and it occurs stereotypically, regardless of the nature of the damage. However, it is characterized by a number of features.

CHARACTERISTICS OF THE INFLAMMATORY RESPONSE
– Regardless of the etiological factor, the inflammatory process has three essential components: alteration (tissue damage), exudation (release of fluid and blood cells from vessels into tissues and organs), and proliferation (multiplication of cellular elements).
– The extent and duration of the injury determine the degree and duration of the inflammatory response. The inflammatory response can be localized – and limited to the area of injury, or systemic (generalized) if the damage is extensive.
– The inflammatory response is classified as acute or chronic based on the speed of the process. Microscopic changes occur in the damaged tissues in both acute and chronic inflammation. These changes cause symptoms which can be observable in clinical practice.
– Local clinical changes in the site of inflammation are known as cardinal signs of inflammation: redness, heat, swelling, pain, and loss of normal tissue function. In more extensive responses, systemic signs of inflammation may also be present (such as fever, intoxication, leukocytosis, etc.).
– Vascular response. Microscopic manifestations of inflammation involve small blood vessels, (or the microcirculatory bed). It includes arterioles, capillaries, and venules in the area of injury, as well as red blood cells, white blood cells, and chemical substances known as biochemical mediators. Under normal conditions, blood and its cellular components flow through the microcirculatory bed. Oxygen and nutrient exchange necessary for the health of surrounding tissues occurs as plasma fluid passes between the endothelium lining the walls of arterioles and capillaries. Plasma is the liquid component of blood, consisting mainly of water and proteins, in which blood cells are suspended. Normally, most of the plasma that passes out of the microcirculatory bed returns to the bloodstream through venules. Lymphatic vessels, in turn, remove excess plasma that does not reenter the blood vessel. These processes are disordered resulting the development of inflammation.
– Ischemia. Initially, a brief reflex constriction of blood vessels occurs in the area of injury.
– Arteriovenous hyperemia. Dilation of the same small blood vessels is then observed for several seconds. Dilation is an increase in the diameter of vessels, caused by biochemical mediators released at the moment of injury. The expansion of the microcirculatory bed vessels leads to an enhancement of blood flow through them. The enhanced blood flow filling the capillary bed in the damaged tissue is known as hyperemia. Hyperemia contributes to the appearance of two clinical signs of inflammation: erythema and heat. Erythema, or redness, is easily noticeable in most inflamed tissues of the oral and facial area, while localized temperature changes are more difficult to detect.

Exudation: the release of fluid and blood cells from vessels into tissues and organs.
Key Mechanisms of Development:
– Increased Permeability: During hyperemia, the permeability of the vessels in the microcirculatory bed increases, making blood vessels «leaky.» Endothelial cells contract, creating gaps between them. As a result, plasma fluid with low protein content, devoid of cells, passes between the endothelial cells and enters the tissues. This fluid is called transudate and is similar to the type of fluid that typically moves from the microcirculatory bed into tissues to supply oxygen and nutrients. The loss of fluid from the microcirculatory bed leads to an increase in blood viscosity. The blood becomes thicker and cannot flow as easily, ultimately resulting in a reduced flow through the microcirculatory bed.
– Leukocyte Emigration: As blood flow slows down, red blood cells begin to accumulate in the center of the blood vessels, while leukocytes migrate to the periphery of the vessels. This movement of leukocytes to the periphery is called margination. Leukocytes are now able to adhere to the inner walls of the damaged blood vessels, which have become «sticky» due to specific factors on the cell surfaces. This process is known as leukocyte pavementing. Subsequently, leukocytes begin to exit the vessels into the damaged tissues, accompanied by a significant amount of fluid. The emigration of leukocytes into the damaged tissues is facilitated by the opening of intercellular junctions between the endothelial cells lining the blood vessels; these cells contract in response to biochemical mediators. As leukocytes (primarily neutrophils) migrate through the walls of blood vessels and the surrounding basement membrane, they further increase the permeability of the microcirculatory bed, allowing larger molecules and other cells to exit.

Formation of Exudate
The fluid that now passes into the damaged tissues is called exudate. This fluid contains cells and a higher concentration of protein molecules than transudate. The presence of both transudate and exudate in the damaged tissue promotes the dissolution of harmful agents that may be present and facilitates the transport of these agents through the lymphatic vessels to lymph nodes, which stimulates an immune response. As transudate passes into the tissues, excess fluid begins to accumulate in the connective tissue at the site. Excess fluid that is accumulated in the interstitial space is called edema which is manifested as localized swelling, another cardinal sign of inflammation.
In case of further damage, exudate may seep out of the tissue either as a clear, watery fluid (serous exudate) or as thick pus ranging from white to yellow in color, containing tissue debris and a large number of leukocytes (purulent exudate). The accumulation of purulent exudate in a limited cavity is defined as abscess. The formation of exudate can be so excessive that it hinders tissue repair. Excessive accumulation of exudate can lead to the formation of fistulas and sinus tracts. These drainage channels develop in the healthy, functioning tissue that replaces necrotic cells, allowing the excess exudate to drain out.
In some cases, the excessive exudate in the damaged tissues may require mechanical drainage, often by making an incision in the swollen area and placing a drainage tube in the incision site. This drainage procedure may be accompanied by the administration of antibiotics and anti-inflammatory drugs. The formation of exudate also leads to another clinical sign of inflammation – pain, as the exudate exerts compression of the sensory nerves in the area. Additionally, certain biochemical mediators that are present in the inflamed tissue can contribute to the sensation of pain. The edema and pain in tissues occurring as a result of the inflammatory process may then lead to a loss of normal tissue function, which is another cardinal sign of inflammation.

Leukocyte Chemotaxis
Chemotaxis is defined as directed movement of leukocytes along a concentration gradient of biochemical mediators (known as chemotactic factors or chemoattractants), which enhance this movement. The emigration and chemotaxis of leukocytes to the site of inflammation protect the tissue from further damage. Initially, leukocytes form the so called leukocyte barrier, effectively isolating the site of injury from the surrounding healthy tissue. Later, in the damaged tissue, leukocytes perform phagocytosis, which involves the capture and removal of foreign substances. These foreign substances may include pathogenic microorganisms or tissue remains. The presence of such substances interferes with the healing process, therefore they must be removed so that inflammation resolves and tissue regeneration begins.

THE ROLE OF OXYGEN METABOLISM DISORERS IN INFLAMMATION
In addition to the role of pathogenic factors and the activation of the immune response, as previously discussed, it is important to highlight some specific aspects of oxygen metabolism disturbances in the pathogenesis of periodontal inflammation.
In case of periodontitis, oxygen consumption increases, leading to a rise in the concentration of reactive oxygen species (ROS) and the development of oxidative stress (lipid peroxidation). Lipid peroxidation directly damages periodontal tissue, contributing to its degradation. It also has a significant indirect effect on the qualitative properties of saliva, against the background of functional changes in the salivary glands. Oxidative stress may also result from the dysfunction of antioxidant systems, such as insufficient glutathione regeneration or a deficiency of antioxidant enzymes. These processes often precede microcirculatory disorders, further exacerbating the inflammatory process.

THE ROLE OF MICROFLORA IN THE DEVELOPMENT OF ORAL DISEASES

Throughout a person’s life, the body is inhabited by a huge number of various bacteria. The roles of these bacteria can vary from beneficial to harmful, while some bacteria may have no noticeable effects. It is estimated that at least 700 species of microorganisms are present in the human oral cavity. Fortunately, the majority of these microorganisms maintain in the ecological balance and do not cause diseases. This is a normal part of the oral environment, playing a crucial role in protecting against the colonization of external bacteria that could affect systemic health. However, it is important to note that the most common oral diseases – dental caries, gingivitis, and periodontitis – are primarily caused by microorganisms. Nevertheless, bacteria are a necessary but not sufficient condition for the development of these diseases. Environmental conditions (particularly those related to the host) are generally considered to play a key role in the pathogenesis of these diseases. The same applies to infections by fungi of the genus Candida; most individuals carry this fungus, but oral candidiasis occurs relatively rarely.
The role of periodontal diseases as a risk factor in the development and/or progression of systemic conditions such as diabetes mellitus, rheumatoid arthritis, cardiovascular diseases, adverse pregnancy outcomes, and head and neck cancers has been the subject of extensive research in recent years.
Three primary mechanisms linking oral infections with systemic pathology have been revealed:
– The spread of infection from the oral cavity due to transient bacteremia,
– The circulation of microbial toxins,
– Systemic inflammation triggered by adverse immune responses to oral microorganisms.

CONCEPT OF BIOFILM
Periodontal diseases share many associative and cause-and-effect relationships with systemic diseases and may increase susceptibility to them through common risk factors, such as the presence of pathogenic Gram-negative anaerobic microorganisms in subgingival biofilms and the transformation of the periodontium into a reservoir for inflammatory mediators.
Under natural conditions, microorganisms can exist either as planktonic (free-floating) cultures or as biofilms. For the past 100 years, research activity has primarily focused on planktonic bacterial cultures; however, it is now widely recognized that microorganisms in the oral cavity are organized in the form of biofilms.

BIOFILM FORMATION
A biofilm is an accumulation of bacteria that exist as closely connected communities, adhering to various types of surfaces (both natural and artificial), typically in an aquatic environment containing sufficient concentrations of nutrients necessary to support the metabolic needs of the microbiota (Listgarten MA, 1999). Based on this definition, we can note that dental plaque has common characteristics with a biofilm. The oropharynx is an open ecosystem where bacteria are constantly present, seeking to colonize all favorable areas. Preferred targets for bacterial colonization include the hard and soft palate, subgingival and supragingival surfaces, teeth, lips, cheeks, and tonsils. Most bacteria can persist after biofilm formation on non-shedding surfaces, i.e., hard tissues (tooth and root surfaces, restorative materials, implants, dentures, etc.).
In conditions of healthy dental and gingival relationships, there is a balance between the additive and retention mechanisms of biofilms on the one hand, and the abrasive forces that tend to reduce biofilm formation (e.g., self-cleaning by the cheeks and tongue, dietary habits, and mechanical oral hygiene practices) on the other. Disruption of this ecosystem balance (due to its overload or weakening of immune mechanisms) may become a problem not only at the local level but also systemically. Therefore, the gold standard in the prevention of diseases associated with the pathogenic impact of microorganisms is the direct removal of biofilms from teeth, restorations, or dentures through regular tooth brushing.

Biofilm formation
Within minutes after thorough cleaning the tooth surface, a thin film (pellicle) forms. It is composed of proteins and glycoproteins found in saliva. The subsequent formation of the biofilm (dental plaque) occurs as follows:
– Association (Binding): Due to purely physical forces, bacteria freely bind to the thin pellicle.
– Adhesion (Sticking): Individual bacteria, having special surface molecules (adhesins), attach to receptors on the tooth surface. These bacteria are called «primary colonizers,» with examples including Streptococci and Actinomyces. Subsequently, other microorganisms join these primary colonizers.
– Bacterial Proliferation: Once attached, the bacteria begin to actively proliferate, increasing the bacterial population in the biofilm.
– Formation of Microcolonies: Over time, the bacteria aggregate into microcolonies. Many Streptococci secrete protective polysaccharides that help them solidify their attachment.
– Biofilm Formation: These microcolonies become a part of a complex structure known as a biofilm or «attached dental plaque.» Within this structure, bacteria gain metabolic advantages.
– Growth and Maturation of Dental Plaque: The dental plaque starts to function as a complex system with its own primitive «circulatory system.» As the plaque matures, the number of anaerobic bacteria increases. Metabolic byproducts and cell wall components causes a response from the human immune system. Due to the biofilm structure, the bacteria inside it are protected from phagocytic cells and external bactericidal agents.

FACTORS INFLUENCING THE FORMATION OF MICROFLORA
The formation of the oral microflora is influenced by numerous factors that contribute to the selection of microorganisms and the maintenance of balance among bacterial populations. These factors are as follows:
– The condition and structural features of the oral mucosa
– Temperature and pH of the oral cavity
– Salivation
– Condition of the teeth
– Diet composition
– Oral hygiene
– The natural resistance of the body
The oral microflora consists of a wide range of microorganisms. Some of these microorganisms are permanently present in the oral cavity and are called autochthonous microflora, while others, known as allochthonous microflora, originate from other parts of the body. The autochthonous microflora is further divided into resident (permanent) and transient (temporary) species. Resident flora consists of relatively stable bacterial species specific to a given biotope and the age of the host organism, and it quickly recovers after disturbances. Transient flora colonizes the oral cavity for a short period of time and, since it includes not only non-pathogenic but also opportunistic microorganisms, it can cause some diseases if the balance with resident flora is disordered. Allochthonous microflora includes microbes that are typically found in other parts of the body, such as the intestines and nasopharynx.

THE ROLE OF ORAL MICROFLORA
The normal microflora of the oral cavity plays a critical role in human health:
– Stimulates the development of lymphoid tissue.
– Inhibits the proliferation of pathogenic bacteria through competition for resources, alteration of the environmental acidity, and synthesis of substances with damaging effects, such as alcohols and hydrogen peroxide. For example, Lactococcus lactis, a bacterium that is a part of the normal microflora, can produce nisin, a bacteriocin that prevents tumor formation in the oral cavity and increases the lifespan of tumor-bearing mice.
– Maintains a healthy level of inflammation in the mucosa and helps the immune system to respond to various threats by providing a balance between inflammatory and anti-inflammatory processes.
– Facilitates self-cleaning of the oral cavity.
– Provides the body with essential amino acids and vitamins released by microorganisms during their metabolism. The oral microbiome also participates in the systemic circulation of nutrients, particularly through nitrate metabolism. Nearly 25% of ingested nitrates are transported via the enterosalivary circuit to the oral cavity, where oral microbes convert nitrate into nitrite, which enters the bloodstream during digestion and is converted into nitric oxide. Nitric oxide is important for cardiovascular health, as it has vasodilatory and hypotensive effects. Thus, the normal oral microflora is essential not only for maintaining oral health but also for supporting systemic health.
– Stimulates the secretion of salivary and mucous glands through the metabolic products produced by microorganisms.

IMMUNE MECHANISMS OF THE ORAL CAVITY

The oral cavity serves as a gateway to both the gastrointestinal and respiratory tracts, it consists of complex anatomical structures, and it is constantly exposed to antigens from the air and food. Various microorganisms colonize the environments provided by these structures. The rich community of symbiotic microbes and their metabolites, continuous tissue damage from chewing, antigens from food, and airborne particles present a potential problem for the homeostasis of the oral mucosa. Consequently, the mucosal surface and its inherent immune system are necessary to protect the internal environment of the body. The association between the epithelium and the innate and adaptive immune mechanisms is of the fundamental significance for the rapid recognition and effective elimination of pathogens on the epithelial surface. The mucosal immune system operates in two directions: preventing pathogen invasion and defending against foreign antigens, while simultaneously maintaining immunological tolerance toward symbiotic microorganisms and various harmless substances that contact the oral mucosa.
The oral cavity is an entry point for many microorganisms from the environment, therefore its protective functions are of paramount importance. The oral cavity hosts an active and complex immune defense system. The teeth and surrounding mucosa are continuously bathed in saliva, produced by both the major and minor salivary glands. Saliva is a watery fluid secreted by the salivary glands, containing numerous innate antimicrobial agents (immunoglobulins IgA, IgM, and IgG, as well as antimicrobial peptides like histatins, lysozyme, lactoferrin, peroxidases, and SLPI – secretory leukocyte protease inhibitor). It has been observed that patients with reduced saliva production have an increased susceptibility to oral candidiasis. In the area of the gingival crevice, which surrounds the crown of the tooth, gingival crevicular fluid is released. This fluid contains leukocytes, sIgA, complement system proteins, and other plasma components. As it penetrates the gingiva, it fills the gingival sulcus and flows along the teeth. During inflammation, the diffusion of gingival fluid accelerates.
Local Defense or Colonization Resistance
Local defense, also known as colonization resistance, is a complex protective system that has developed through evolution Its main task is the protection of mucous membranes being in direct contact with the external environment. The primary function of this system is to maintain the constancy of the internal environment of the body. Thus, the local immune system acts as the first line of defense against foreign substances and microorganisms.
The local immunity of the oral cavity has two main functions: the barrier-protective function and the protective function of saliva. In its turn, each of them is divided into non-specific and specific defense factors.

NON-SPECIFIC IMMUNE FACTORS
Non-specific protection of the oral cavity comprises a set of mechanical, chemical, and physiological processes that are independent of the recognition of the antigenic structure of incoming microbes.
Non-Specific Barrier Factors:
– Mucous membrane
– Normal microflora (colonization resistance)
– Leukocytes
– Desquamation of buccal epithelium

The Mucous Membrane as a Barrier
The intact mucous membrane serves as a barrier to most microbes. Epithelial cells are in constant contact with the bacterial products of supra- and subgingival biofilms on the tooth surface, as well as with bacteria attached to the mucosal surfaces. Oral keratinocytes and dendritic cells in the oral mucosa, through Toll-like receptors (TLRs), differentiate between commensal and pathogenic microorganisms and mediate the generation of protective immunoinflammatory responses to potentially invading pathogens or promote immune tolerance to commensal microorganisms. Activation of Toll-like receptors is a signal for epithelial cells to produce cytokines, chemokines, and peptide antibiotics, primarily β-defensins. More than 45 different antimicrobial peptides have been identified in human saliva and gingival crevicular fluid. These peptides are produced by salivary glands and epithelial cells, forming a continuous layer on the mucosal surfaces. Defensins, cathelicidins (LL-37), calprotectins, and histatins are the primary antimicrobial peptides found in the oral cavity. Their main function is to prevent bacterial, fungal, or viral adhesion and infection. In addition to their antimicrobial activity, these peptides are involved in several other important processes in host tissues, such as wound healing, cell proliferation, and chemotaxis of immune cells.
The epithelium is constantly renewed by cell division in the deeper layers, and this turnover occurs more rapidly in the mucosa than in masticatory areas. The formation of cells in the deeper epithelial layers is balanced by the loss of cells from the surface. The rapid shedding of surface cells acts as a protective mechanism, limiting the colonization and invasion of microbes adhering to the mucosal surface. Thus, the oral epithelium provides the first line of defense against various environmental agents and microbes.

Role of Normal Microflora
The oral cavity hosts unique microflora that plays a key role in the natural defense of the mucous membranes against external microbes. These normal microorganisms (commensal bacteria) compete with external bacteria for nutrients, oxygen, and adhesion sites. Lipopolysaccharides produced by these endogenous microorganisms activate the immune system and stimulate antibody synthesis. If the normal microflora is depressed, for example, due to antibiotic or glucocorticoid use, it may lead to the excessive proliferation of potentially harmful bacteria and fungi on the mucous membranes.

Protective Role of Saliva
Saliva contains numerous antimicrobial components that protect the oral cavity against possible microbial colonization and subsequent infection. These factors include peroxidase, lysozyme, lactoferrin, cystatin, and SLPI (secretory leukocyte protease inhibitor). There are also specific peptides, such as histatins, cathelicidin (LL-37), and α- and β-defensins, which are secreted by the salivary glands and their ducts. These peptides not only provide antimicrobial protection but also enhance the mechanisms of both innate and adaptive immune responses.

Non-Specific Defense Factors in Saliva
Saliva contains several non-specific defense factors that are essential for protecting the oral cavity from microbial colonization and infection:
– Lysozyme: An enzyme that destroys bacterial cell walls.
– Lactoferrin: A protein that binds iron and possesses antimicrobial properties.
– Peroxidase: An enzyme that contributes to the destruction of microorganisms.
– Beta-lysins: Antimicrobial peptides.
– Tetrapeptide sialin: A compound with antimicrobial activity.
– Acidic glycoproteins: Proteins that prevent microorganisms from adhering to surfaces.
– Nucleases: Enzymes that cleave DNA and RNA.
– Mucin: A glycoprotein that provides viscosity of saliva and protects mucosal surfaces.
– Interferon: A protein with antiviral activity.

Mechanisms of Action
The enzymes acting on the bacterial cell walls, include lysozyme that affects Gram-positive bacteria, preventing their adhesion and growth. Peroxidase system of saliva including salivary peroxidase and myeloperoxidase is cytotoxic for bacteria and it inhibits their growth and production of acids, functioning synergistically with other molecules.
The primary target of lysozyme is peptidoglycan, a glycosidic polymer and a structural component of bacterial cell walls, which provides bacteria with shape and osmotic stability. Lysozyme can directly kill some bacteria by degrading this peptidoglycan layer. Although most bacteria do not die immediately, they become more susceptible to other antimicrobial agents and osmotic stress. Lysozyme damages microbes through at least three different mechanisms:
– Enzymatic cleavage: Lysozyme breaks down bacterial peptidoglycan.
– Cationic protein activity: Lysozyme acts as a small cationic protein, releasing autolytic enzymes from bacteria.
– Amphipathic properties: As a cationic and amphipathic protein (containing both hydrophobic and hydrophilic groups), lysozyme destroys bacterial membranes.
Although the bactericidal activity of lysozyme against many pathogenic bacteria is relatively weak, especially against Gram-negative bacteria, its effectiveness is significantly enhanced by other host defense substances, such as lactoferrin, antibody-complement complexes, or hydrogen peroxide-ascorbic acid. Presumably, these cofactors disrupt the outer membrane of Gram-negative bacteria, providing lysozyme with access to the sensitive peptidoglycan layer.
Glycoproteins, such as mucin, cover the epithelial surface, creating a protective barrier that prevents the penetration of various particles and infectious agents; they also protect the underlying epithelial layers. Mucins serve as a source for secretory IgA, contributing to immune defense.

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