Inflammation is a response of vascularized tissues to infections, foreign invaders, and damaged tissues that brings cells and molecules of host defines from the circulation to the sites where they are needed, in order to eliminate the offending agents. Inflammation generally is a defensive response that is essential for survival, where mediators of this response include phagocytic leukocytes and cytokines/substances produced by them, antibodies, and complement proteins. Most of these mediators normally circulate in the blood, from which they can be rapidly recruited to any site in the body;some of the cells also reside in tissues. The process of inflammation delivers these cells and proteins to damaged or necrotic tissues and foreign invaders, and activates the recruited cells and molecules, which then function to get rid of the harmful or unwanted substances. Without inflammation, infections would go unchecked, wounds would never heal, and injured tissues might remain permanent festering sores.
On the other hand, the primary function of the inflammatory response is to eliminate a pathogenic insult and remove injured tissue components, thus allowing tissue repair to take place. In teleologic terms, the body attempts to contain or eliminate offending agents to protect tissues, organs and, ultimately, the whole body from damage. Specific cells are imported to attack and destory injurious agents, enzymatically digest and remove them, or wall them off. In the process, damaged cells and tissues are digested and removed to allow repaire to occur.
Causes of Inflammation
Inflammatory reactions may be triggered by a variety of stimuli, including:
1.Infections (bacterial, viral, fungal, parasitic, rickettsiaceae and so on) and microbial toxins are among the most common and medically important causes of inflammation. Different infectious pathogens elicit varied inflammatory responses, from mild acute inflammation that causes little or no lasting damage and successfully eradicates the infection, to severe systemic reactions that can be fatal, to prolonged chronic reactions that cause extensive tissue injury. The outcomes are determined largely by the type of pathogen and, to some extent, by characteristics of the host that remain poorly defined (relative post: http://forum.tomhsiung.com/pharmacy-practice/pharmacotherapy/416-severe-sepsis-septic-shock.html).
PS: In the article of NEJMra1208623, the specific response in any patient depends on the causative pathogen (load and virulence) and the host (genetic characteristics and coexisting illnesses), with differential responses at local, regional, and systemic levels.
2.Tissue necrosis elicits inflammation regardless of the cause of cell death, which may include ischemia (reduced blood flow, the cause of myocardial infarction, etc.) trauma, and physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals). Several molecules released from necrotic cells are known to trigger inflammation。
3.Foreign bodies (splinters, dirt, sutures) may elicit inflammation by themselves or because they cause traumatic tissue injury or carry microbes. Even some endogenous substances can be considered potentially harmful if large amounts are deposited in tissues; such as substances include urate crystals (in the disease gout), cholesterol crystals (in atherosclerosis), and lipids (in obesity-associated metabolic syndrome).
4.Immune reactions (also called hypersensitivity) are reactions in which the normally protective immune system damages the individual's own tissues. The injurious immune responses may be directed against self antigens, causing autoimmune diseases, or may be inappropriate reactions against microbes. Also, the textbook of Drug-Induced Diseases by James E. Tisdale, PharmD, describes the hypersensitivity as reactions mediated by the immune system. In inflammations caused by immune reactions or hypersensitivity, self and environmental antigens act as the triggers of inflammations and since that these stimuli cannot be eliminated, autoimmune and allergic reactions tend to be persistent and difficult to cure, and they are often associated with chronic inflammations.
On the other hand, inflammation could be described as the result of tissue injury.
Cell must be able to adapt to fluctuating environmental conditions (e.g., temperature, solute concentrations, oxygen supply, noxious agents, etc.). The evolution of multicellular organisms eased the precarious lot of individual cells by establishing a controlled extracellular environment where the "inner" environmental conditions remain relatively constant. If a change in the environment is too huge, a cell can be injuried; and if the injury exceeds the cell's adaptive capacity, the cell dies. A cell exposed to persistent sublethal injury has limited available responses, expression of which we interpret as cell injury.
All cells have efficient mechanisms to deal with shifts in environmental conditions. When environmental changes exceed the cell's capacity to maintain normal homeostasis, we recognize acute cell injury. If these stress is removed in time or if the cell can withstand the assault, the damage is reversible, and complete structural and functional integrity is restored. For example, when circulation to the heart is interrupted for less than 30 minutes, all structural and functional alterations prove to be reversible. The cell can also be exposed to persistent sublethal stress, as in mechanical irritation of the skin or exposure of the bronchial mucosa to tobacco smoke. Cell have time to adapt to reversible injury in a number of ways, each of which has a morphologic counterpart. On the other hand, if the stress is sufficiently severe, irreversible injury leads to cell death. The moment when reversible injury becomes irreversible injury, the "point of no return," is not known at present.
The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. The most important inflammation mediators include vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation. These mediators induce various components of the inflammatory response typically by distinct mechanisms, which is why inhibiting each has been therapeutically beneficial. However, there is also some overlap (redundancy) in the actions of the mediators.
The inflammation mediators have some common characteristics, like
Mediators are either secreted by cells or generated from plasma proteins. Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesised de novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are the sentinels that detect invaders and damage in tissues, that is, macrophages, dendritic cells, and mast cells, but platelets, neutrophils, endothelial cells, and most epithelia can also be induced to elaborate some of the mediators. Plasma derived mediators (e.g., complement proteins) are produced mainly in the liver and are present in the circulation as inactive precursors that must be activated. When activated a series of proteolytic and protein-protein interactions are initiated that ultimately to acquire their biologic properties.
Ative mediators are produced only in response to various stimuli. These stimuli include microbial products and substances released from necrotic cells. Some of the stimuli trigger well-defined receptors and signalling pathways.
Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. There is thus a system of checks and balances that regulates mediator actions.
One mediator can stimulate the release of other mediators. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying or, in certain instances, counteracting the initial action off a mediator.
A detail about inflammation mediators can be found here, .
The Process of Inflammation
The steps of the inflammatory response can be divided as the five sections: 1.recognition of the injurious agent;2.recruitment of leukocytes;3.removal of the agent;4.regulation (control) of the response;and 5.resolution (repair).
When an individual encounters an injurious agent, as described above, phagocytes that reside in all tissues try to eliminate these agents. At the same time, phagocytes and other sentinel cells in the tissues recognise the presence of the inflammation triggers and react by liberating cytokines, lipid messengers, and other mediators of inflammation. Some of these mediators act on small blood vessels in the vicinity and promote the efflux of plasma and the recruitment of leukocytes (as demonstrated as dilation of small vessels leading to an increase in blood flow [vasodilation/resulting in more blood cells and plasma proteins], increased permeability of the endothelia, and emigration and accumulation of the leukocytes [stasis]) to the site where the offending agent is located.
PS: the following figure shows the inherent differences between exudate and transudate. Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate. Purulent is a inflammatory exudate rich in leukocytes, the debris of dead cells and, in many cases, microbes.
Recognition of Inflammation-Causative Substances
Cellular Receptors for Microbes
Several cellular receptors and circulating proteins are capable of recognising microbes and products of cell damage and triggering inflammation. Cells express receptors in the plasma membrane, the endosomes (note, it's not the lysosomes), and the cytosol that enable the cells to sense the presence of foreign invaders in any cellular compartment. The most-documentted such receptors are the family of Toll-like receptors (TLRs). These receptors are expressed on many cell types, including epithelial cells, dendritic cells, macrophages, and other leukocytes. Engagement of these receptors triggers production of molecules involved in inflammation, including adhesion molecules on endothelial cells, cytokines, and other mediators.
All cells have cytosolic receptors that recognise a diverse set of molecules that liberated or altered as a consequence of cell damage. These molecules include uric acid, ATP, reduced intracellular K+ concentrations, even DNA when it is released into the cytoplasm and not sequestered in nuclei, as it should be normally, and many others. These receptors activate a multi protein cytosolic complex called inflammasome which induces the produce of the cytokine interleukin-1 (IL-1).
In addition to directly recognising microbes, many leukocytes express receptors for the Fc tails of antibodies and for complement proteins. It is likely that the binding of antibodies and complement proteins by microbes will change the conformation of the Fc tails and activated complement proteins, respectively, and this change of conformation provides the chance of them to bind these leukocyte receptors. These receptors recognise microbes coated with antibodies and complement and promote ingestion and destruction of the microbes as well as inflammation. Some circulating proteins like complements reacts against microbes and produces mediators of inflammation. These proteins act indirectly to the recognition of inflammation-causative substances, with the help of which the cells recognise these substances more effectively.
Reactions of Blood Vessels in Acute Inflammation
The vascular reactions of acute inflammation consist of changes in the flow of blood and the permeability of vessels, both designed to maximise the movement of plasma proteins and leukocytes out of the circulation and into the site of infection or injury. Vasoactive mediators originating from plasma and cells are generated at sites of tissue injury. These vasoactive molecules bind specific receptors on vascular endothelial and smooth muscle cells, causing vasoconstriction or vasodilation. Vasodilation of arterioles increases blood flow and exacerbates fluid leakage into the tissue. Vasoconstriction of postcapillary venules increases capillary bed hydrostatic pressure, further stimulating edema formation. Also vasoactive mediators bind specific receptors on endothelial cells, causing reversible endothelial cell contraction and gap formation.
Changes in Vascular Flow and Caliber
Changes in vascular flow and caliber begin early after injury and consist of the following. Vasodilation is induced by the action of several mediators, notably histamine, on vascular smooth muscle. It is one of the earliest manifestations of acute inflammation. Vasodilation first involves the arterioles and then leads to opening of new capillary beds in the area. The result is increased blood flow, which is the cause of heat and redness.
PS: Critical Closing Pressure & Active/Inactive Capillaries
In rigid tubes, the relationship between pressure and flow of homogeneous fluids is liner, but in thin-walled blood vessels in vivio it is not. When the pressure in a small blood vessel is reduced, a point is reached at which no blood flows, even though the pressure is not zero. This is because the vessels are surrounded by tissues that exert a small but definite pressure on them, and when the intraluminal pressure falls below the tissue bpressure, they collapse. The threshold press is called critical closing pressure.
So in resting tissues, most of the capillaries are collapsed, these capillaries are inactive cappliaries. In active tissues, the metarterioles and the precapillary sphinctersdilate. The result is that the intracapillary pressure rises, overcoming the critical closing pressure of the vessels, and blood flows through all of the capillaries. Relaxation of the smooth muscle of the metarterioles and precapillary sphincters is due to the action of vasodilator metabolites formed in active tissue.
Vasodilation is quickly followed by increased permeability of the microvasculature, with the outpouring of protein-rich fluid into the extravascular tissues. The loss of fluid caused by increased permeability and the increased vessel diameter lead to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood. These changes result in engorgement of small vessels with slowly moving red cells, a condition termed stasis, which is seen as vascular congestion and localised redness of the involved tissue.
As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium. At the same time endothelia cells are activated by mediators produced at sites of infection and tissue damage, and express increased levels of adhesion molecules. Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue.
Increased Vascular Permeability (Vascular Leakage)
Several mechanisms are responsible for the increased permeability of post capillary venules, a hallmark of acute inflammation. These mechanisms of increased vascular permeability are described separately, all probably contribute in varying degrees in responses to most stimuli. For example, at different stages of a thermal burn, leakage results from chemically mediated endothelial contraction and direct and leukocyte-dependent endothelia injury. The vascular leakage induced by these mechanisms can cause life-threatening loss of fluid in severely burned patients.
Contraction of endothelial cells resulting in increased inter endothelial spaces is the most common mechanisms of vascular leakage. It is elicited by histamine, bradykinin, leukotrienes, and other chemical mediators. It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15 to 30 minutes). In some forms of mild injury (e.g., after burns, irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours and lasts for several hours or even days;this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.
Endothelial injury, resulting in endothelia cell necrosis and detachment. Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or is induced by the actions of microbes and microbial toxins that target endothelial cells. Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damage vessels are thromboses or repaired.
Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve intracellular channels that may be stimulated by certain factors, such as vascular endothelial growth factor (VEGF), that promote vascular leakage. However, the contribution of this process to the vascular permeability of acute inflammation is uncertain.
PS: In addition to blood vessels, lymphatic vessels also participate in acute inflammation. The system of lymphatics and lymph nodes filters and polices the extravascular fluids. Lymphatics normally drain the small amount of extravascular fluid that has seeped out of capillaries. In inflammation, lymph flow is increased and helps drain deem fluid that accumulates because of increased vascular permeability. In addition to fluid, leukocytes and cell debris, as well as microbes, may find their way into lymph. Therefore the lymphatics may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis). Inflamed lymph nodes are often enlarged because of hyperplasia of the lymphoid follicles and increased numbers of lymphocytes and macrophages. This constellation of pathologic changes is termed reactive, or inflammatory, lymphadenitis. For clinicians the presence of red streaks near a skin would is telltale sign of an infection in the wound. This streaking follows the course of the lymphatic channels and is diagnostic of lymphangitis;it may be accompanied by painful enlargement of the draining lymph nodes, indicating lymphadenitis.
Leukocyte Recruitment to Sites of Inflammation
The changes in blood flow and vascular permeability are quickly followed by an influx of leukocytes into the tissue. The most important leukocytes in typical inflammatory reactions include neutrophils and macrophages, both termed phagocytosis. These leukocytes (but no limited to) ingest and destroy bacteria and other microbes, as well as necrotic tissue and foreign substances. Leukocytes also produce growth factors that aid in repair.
But a price that is paid for the defensive potency of leukocytes is that, when strongly activated, they may induce tissue damage and prolong inflammation, because the leukocyte products that destroy microbes and help "clean up" necrotic tissues can also injure normal bystander host tissues.
The journey of leukocytes from the vessel lumen to the tissue is a multistep process that is mediated and controlled by adhesion molecules and cytokines called chemokines. Briefly, the recruitment of leukocyte to sites of inflammation is a multistep process, which can be divided into adhesion to endothelium, migration through endothelium, and chemotaxis.
Leukocyte Adhesion to Endothelium
The whole process includes the margination, rolling, and adhesion of leukocytes to endothelium. In normal and unactivated status, vascular endothelium does not bind circulating cells or impede their passage. In inflammation, the endothelium is activated and can bind leukocytes as a prelude to their exit from the blood vessels, which follows those mechanisms below.
In normally flowing blood in venues, red cells are confined to a central axial column, displacing the leukocytes toward the wall of the vessel. Because blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreaes), and more white cells assume a peripheral position along the endothelial surface. This process of leukocyte redistribution is called margination. Subsequently, leukocytes adhere transiently to the endothelium, detach and bind again, thus rolling on the vessel wall. Finally the cells come to rest at some point where they adhere firmly (adhesion).
The attachment of leukocytes to endothelial cell is mediated by complementary adhesion molecules on the two cell types (leukocytes and endothelium) whose expression is enhanced by cytokines. The two major families of molecules involved in leukocyte adhesion and migration are the selections and interns, and their ligands.
Table 1 Endothelia and Leukocyte Adhesion Molecules
The initial rolling interactions are mediated by a family of proteins called selectins. There are three types of selectins: L-selectin expressed on leukocytes, E-selectin expressed on endothelium, and P-selectin expressed in platelets and on endothelium. There are ligands for each selectin, which are expressed on leukocytes and endothelium, respectively. The expression of selecting and their ligands is regulated by cytokines produced in response to infection and injury. Within 1 to 2 hours the endothelial cells begin to express E-selectin and the ligands for L-selectin. Other mediators such as histamine and thrombin stimulate the redistribution of P-selectin from its normal intracellular stores in endothelial cell granules (called Weibel-Palade bodies) to the cell surface.
The interactions between selections and their ligands are low-affinity with a fast off-rate, and they are easily disrupted by the flowing blood. As a result, the bound leukocytes bind, detach, and bind again, and thus begin to roll along the endothelial surface.
These weak rolling interactions slow down the leukocytes and give them the opportunity to bind more firmly to the endothelium. Firm adhesion is mediated by a family of heterodimeric leukocyte surface proteins called integrins such as VLA-4, LFA-1 etc, where they are expressed on leukocytes with ligands such as VCAM-1, ICAM-1, etc. Leukocytes normally express interns in a low affinity state. Chemokines that were produced a the site of injury bind to endothelial cell proteoglycans, and are displayed at high concentrations on the endothelial surface. Meanwhile, these chemokines bind to and activate the rolling leukocytes which induces the conversion of integrins from low-affinity state to hight-affinity state. Finally, high level of ligand on endothelial surface and high -affinity of integrin on leukocytes results in firm integrin-mediated binding of these two cell types at the site of inflammation. The leukocytes stop rolling, their cytoskeleton is reorganised, and the spread out on the endothelial surface.
Leukocyte Migration Through Endothelium
Transmigration of leukocytes occurs mainly in postcapillary venules. Chemokines act on the adherent leukocytes and stimulate the cells to migrate through interendothelial spaces toward the chemical concentration gradient, that is, toward the site of injury or infection where the cheekiness are being produced. Several adhesion molecules present in the intercellular junctions between endothelia cells are involved in the migration of leukocytes, including a member of the immunoglobulin superfamily called CD31 or PECAM-1 (platelet endothelial cell adhesion molecule). After traversing the endothelium, leukocytes pierce the basement membrane, probably by secreting collagenases, and enter the extravascular tissue. The cells then migrate toward the chemotactic gradient created by cheekiness and other chemoattractants and accumulate in the extravascular site.
Chemotaxis of Leukocytes
After exiting the circulation, leukocytes move in the tissue word the site of injury by a process called chemotaxis, which is defined as locomotion along a chemical gradient. Both exogenous and endogenous substances can act as chemoattractants. The most common exogenous agents are bacterial products, including peptides that possess an N-formylmethionine terminal amino acid and some lipids. Endogenous chemoattractants include several chemical mediators like: 1.cytokines, particularly those of the chemokine family (e.g., IL-8);2.components of the complement system, particularly C5a;and 3.arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4). All these chemotactic agents bind to specific seven-transmembrane G protein-coupled receptors on the surface of leukocytes. Signals initiated from these receptors result in activation of second messengers (check thread "G Protein-Coupled Receptors" at http://www.tomhsiung.com/wordpress/2014/09/g-protein-coupled-receptors/) that increase cytosolic calcium and activate small guanosine triphosphatases of the Rac/Rho/cdc42 family as well as numerous kinases. These signals induce polymerization of actin, resulting in increased amounts of polymerized actin at the leading edge of the cell and localization of myosin filaments at the back. The leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension, much as an automobile with front-wheel drive is pulled by the wheels in front. The net result is that leukocytes migrate toward the inflammatory stimulus in the direction of the locally produced chemoattractants.
The Nature of the Leukocyte Infiltrate
The nature of the leukocyte infiltrate varies with the age of the inflammatory response and the type of stimulus. In most forms of acute inflammation neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours. There are several reasons for the early preponderance of neutrophils: they are more numerous in the blood than other leukocytes, they respond more rapidly to chemokines, and they may attach more firmly to the adhesion molecules that are rapidly induced on endothelial cells, such as P- and E-selectins. After entering tissues, neutrophils are short-lived;they undergo apoptosis and disappear within 24 to 48 hours. Monocytes not only survive longer but may also proliferate in the tissues, and thus they become the dominant population in prolonged inflammatory reactions.
There are, however, exceptions to this stereotypic pattern of cellular infiltration. In certain infections like those produced by Pseudomonas bacteria, the cellular infiltrate is dominated by continuously recruited neutrophils for several days;in viral infections, lymphocytes may be the first cells to arrive; some hypersensitivity reactions are dominated by activated lymphocytes, macrophages, and plasma cells;and in allergic reaction, eosinophils may be the main cell type.
The complement system is a collection of soluble proteins and membrane receptors that function mainly in host defines against microbes and in pathologic inflammatory reactions. This system of complement functions in both innate and adaptive immunity for defines against microbial pathogens. In the process of complement activation, several cleavage products of complement proteins are elaborated that cause increased vascular permeability, chemotaxis, and opsonization.
Complement system acts as the bridge between innate and adaptive immune system. This concept is due to the fact that complement proteins can be activated directly by antigen-antibody complexes.
There are three main effects of complement: 1.lysis of cells such as bacteria, allografts, and tumor cells; 2.generation of mediators that participate in inflammation and attract neutrophils; and 3.opsonization – enhancement of phagocytosis.
C3b is the central molecule of the complement cascade. It has two core functions: 1.it combines with other complement components to generate C5 convertase, the enzyme that leads to the production of the membrane attack complex (first it adhere to the surface of the targets); and 2.it opsonises bacteria because phagocytes have receptors for C3b on their surface.
How to activate?
In the classic pathway, antigen-antibody complexes activate C12 to form a protease and thereafter the complement cascade starts. In the lectin pathway, MBL (mannas-binding lectin/mannose-binding protein) binds to the surface of microbes bearing mannan. This activates proteases associated with MBL that activates complement cascade. In the alternative pathway, many unrelated cll surface substances can initiate the process by binding C3 and factor B. This complex is cleaved by a protease and finally the complement cascade initiates.
Negative Feedback Mechanisms
Innate and inflammatory responses are regulated by either enhancing or inhibiting mechanisms. The inhibiting mechanisms controls the degree of inflammation and terminate it when appropriate so that the causative substances of inflammation are eliminated while harmful effects to body could be limited to minimize the tissue damage.
In part, inflammation declines after the offending agents are removed simply because the mediators of inflammation are produced in rapid bursts, only as long as the stimulus persists, have short half-lives, and are degraded after their release. On the other hand, as inflammation develops, the process itself triggers a variety of stop signals that actively control and inhibit the inflammatory reaction. Some substances like lipoxins derived from arachidonic acid (AA), transforming growth factor-β (TGF-β), and IL-10 act as anti-inflammatory mediators to obtain the purpose of controlling and inhibiting the inflammation.
A Price Paid to Inflammation
General Symptoms and Signs of Inflammation
Although inflammation serves to protect and control infections and other harmful insults, it can also cause further tissue damage, which is manifested as the disease symptoms of redness, swelling, heat, and pain. The increased blood flow due to vasodilation results in redness and increased temperature in the area. The increased vascular permeability causes blood fluids to leak out of the vessels as the phagocytes transmigrate and thereby also cause edema (swelling) of the surrounding tissue. The source of the pain is still not clearly understood, but it is probably due to the combined effects of cytokines (e.g.,, prostaglandins) and coagulation cascade components on nerve endings in the inflamed region. Bradykinin also appears to increase sensitivity to pain. Pus, a common sign of infection, is composed mainly of dead PMNs and tissue cells.
Although phagocytic cells are effective killers of bacteria and are essential for clearing the invading bacteria from an infected area, the body can pay a high price for this service. During active killing of a bacterium, lysosomal enzymes are released into the surrounding area, as well as into the phagolysosome. Released lysosomal enzymes damage adjacent tissues and can be the main cause of tissue damage that results from a bacterial infection. Also, PMNs kill themselves as a result of their killing activities, and lysosomal granules released by dying PMNs contribute further to tissue destruction.