Fundamaentals of Pathology - INFLAMMATION.pptx

Fundamaentals of Pathology - INFLAMMATION.pptx

1. Fundamentals of Pathology Unit 2 Inflammation By Sujoy Tontubay, Assistant Professor (Allied Health Sciences), ILEAD, Kolkata. B.Sc. (University of Calcutta), M.Sc. in Biomedical Laboratory Science(V.U), Post Graduate Diploma in Epidemiology and Public Health(V.U) Former Guest Lecturer (Medical Laboratory technology) in Guru Nanak Institute of Pharmaceuticals Science and Technology (G.N.I.P.S.T)

2. Inflammation Inflammation is defined as the local response of living mammalian tissues to injury from any agent. It is a body defense reaction in order to eliminate or limit the spread of injurious agent, followed by removal of the necrosed cells and tissues. The injurious agents causing inflammation may be as under: Infective agents like bacteria, viruses and their toxins, fungi, parasites. Immunological agents like cell-mediated and antigen antibody reactions. Physical agents like heat, cold, radiation, mechanical trauma. Chemical agents like organic and inorganic poisons. Inert materials such as foreign bodies.

3. SIGNS OF INFLAMMATION The Roman writer Celsus in 1st century A.D. named the famous 4 cardinal signs of inflammation as: rubor (redness); tumor (swelling); calor (heat); dolor (pain). To these, fifth sign functio laesa (loss of function) was later added by Virchow

4. Types of Inflammation There are two types of inflammation: Acute inflammation:  This is the type you may be more familiar with — it’s the response to sudden body damage, like cutting your finger. To heal the cut, your body sends inflammatory cells to the injury. These cells start the healing process. Acute inflammation may last for a few hours to a few days, depending on your condition. Chronic inflammation:  Your body continues sending inflammatory cells even when there’s no outside danger. For example, in rheumatoid arthritis, inflammatory cells and substances attack joint tissues leading to an inflammation that comes and goes. This can cause pain and severe damage to joints. Chronic inflammation is long term — it lasts for months to years.

5. Symptoms of acute and chronic inflammation Acute inflammation may cause: - Flushed skin at the site of the injury. - Pain or tenderness. - Swelling. - Heat. Chronic inflammation symptoms may be harder to spot than acute inflammation symptoms. Signs of chronic inflammation can include: - Abdominal pain. - Chest pain. - Fatigue and/or insomnia. - Fever. - Joint pain or stiffness. - Mouth sores. - Skin rash. - Depression, anxiety and other mood disorders. - Gastrointestinal issues, like diarrhea, constipation and acid reflux. - Weight gain or weight loss. - Frequent infections.

6. Acute inflammation Acute inflammation is of short duration (lasting less than 2 weeks) and represents the early body reaction, resolves quickly and is usually followed by healing. The main features of acute inflammation are: accumulation of fluid and plasma at the affected site; 2. intravascular activation of platelets; 3. polymorphonuclear neutrophils as inflammatory cells. Sometimes, the acute inflammatory response may be quite severe and is termed as fulminant acute inflammation.

7. Chronic inflammation Chronic inflammation is of longer duration and occurs after delay, either after the causative agent of acute inflammation persists for a long time, or the stimulus is such that it induces chronic inflammation from the beginning.

8. Phases of Acute Inflammation Acute inflammation can be discussed in terms of two stages; (1) the vascular phase, followed by (2) the cellular phase.

9. Vascular events The vessels which show this are arterioles, capillaries and venules.  Vasoconstriction - When there’s an immediate antigen (foreign body e.g. bacteria, viruses, parasites, suture material) invading the body we get a transient arteriolar vasoconstriction as an inflammatory reaction Vasodilation - Vasoconstriction is followed by vasodilation (occurs by chemical mediators) which will lead to a congestion at the area(so this is why we have redness and warmth and stasis at the sight of inflammation). Increased Redness (Rubor) Increased Temperature (Calor)  Mediators of the event are Histamine & Serotonin Increased Vascular Permeability Every blood vessel is lined by endothelial cells. They are positive for CD 34. The fluids (Plasma, plasma proteins, WBCs) exudate, which results in Swelling (Tumor). Exudate: rich in protein. Transudate: poor in protein. Stasis - As stasis develops, leukocytes (principally neutrophils) begin to accumulate along the vascular endothelial surface moving from the center to the periphery of the blood vessel; in a process called margination. When plasma comes out from blood vessels, the RBCs become concentrated. In other words, Viscosity is increased. This results in sluggish blood flow.

10. (a)  Mast cells detect injury to nearby cells and release  histamine initiating an inflammatory response. (b)  Histamine increases blood flow to the wound site, and increased vascular permeability allows fluid, proteins, phagocytes, and other immune cells to enter infected tissue. These events result in the swelling and reddening of the injured site, and the increased blood flow to the injured site causes it to feel warm.  Inflammation is also associated with pain due to these events stimulating nerve pain receptors in the tissue. The interaction of phagocyte PRRs with cellular distress signals and PAMPs and opsonins on the surface of pathogens leads to the release of more proinflammatory chemicals, enhancing the inflammatory response.

11. Vascular changes

12. CELLULAR EVENTS The cellular phase of inflammation consists of 2 processes: exudation of leucocytes; Phagocytosis

13. Cells and mediators of inflammation Meadiators of inflammation Mediators are the substances that initiate and regulate inflammatory reactions. These are: cell derived or plasma protein derived vasoactive amines, lipid products, cytokines, products of complement activation

14. Types of inflammatory cells Types of inflammatory cells include neutrophils, eosinophils, lymphocytes, plasma cells, and histiocytes. Each one of these types of cells has a unique role to play in the body’s defense system.  For example, neutrophils and eosinophils play a more active role in the body’s early or acute response to an infection or injury. In contrast, lymphocytes, plasma cells, and histiocytes typically play a more active role in the prolonged or chronic response to infection or injury

15. Chronic inflammation Chronic inflammation is defined as prolonged process in which tissue destruction and inflammation occur at the same time. Chronic inflammation may occur by one of the following 3 ways: Chronic inflammation following acute inflammation - When the tissue destruction is extensive, or the bacteria survive and persist in small numbers at the site of acute inflammation e.g. in osteomyelitis, pneumonia terminating in lung abscess. 2. Recurrent attacks of acute inflammation - When repeated bouts of acute inflammation culminate in chronicity of the process e.g. in recurrent urinary tract infection leading to chronic pyelonephritis, repeated acute infection of gallbladder leading to chronic cholecystitis. 3. Chronic inflammation starting de novo - When the infection with organisms of low pathogenicity is chronic from the beginning e.g. infection with Mycobacterium tuberculosis.

16. TYPES OF CHRONIC INFLAMMATION Conventionally, chronic inflammation is subdivided into 2 types: Chronic non-specific inflammation - When the irritant substance produces a non-specific chronic inflammatory reaction with formation of granulation tissue and healing by fibrosis, it is called chronic non-specific inflammation e.g. chronic osteomyelitis, chronic ulcer, lung abscess. Chronic granulomatous inflammation - In this, the injurious agent causes a characteristic histologic tissue response by formation of granulomas e.g. tuberculosis, leprosy, syphilis, actinomycosis, sarcoidosis etc.

17. Phagocytosis Phagocytosis is a type of active transport mechanism as it requires the direct use of ATP to fuel the transport. Phagocytosis occurs in almost any tissue, most often in the bloodstream and interstitial space. Phagocytosis is a complex phenomenon involving a cascade of multiple molecular mechanisms. So, the cells need to undergo specific steps in order to phagocytize something.

18. Steps / Mechanism of Phagocytosis There are eight stages or steps involved in phagocytosis. They are described below: Step 1: Activation of the Phagocyte It is the first step of phagocytosis when the resting phagocytes become activated. During this phase, the phagocytes come close to some inflammatory mediators like bacterial proteins, capsules, peptidoglycan, prostaglandins, and complement proteins. As a result, the receptors on the cell surface bind to these molecules and cause the cells to respond. Consequently, the phagocytes switch to a higher energy level. This phenomenon usually involves rearranging the cell cytoskeleton and swelling of the cell (caused by calcium and sodium ion influx). Phagocytes also produce pattern recognition receptors (PRRs) which recognize and bind to pathogen-associated molecular patterns (PAMPs). PAMPs are components of pathogens and can include molecules like peptidoglycan and lipopolysaccharide (LPS).

19. Step 2: Chemotaxis of the Phagocyte  In the next step, the directional movement of the phagocyte occurs toward a higher concentration of molecules under the influence of a chemical attractant called chemotaxin . Bacterial products (e.g., endotoxin), injured tissues, complement proteins, and chemical substances produced by WBCs are typical examples of chemotaxin . Activated cells express more glycoprotein receptors that help them reach the site of infections and bind firmly with microorganisms under the influence of cytokines.  Step 3: Attachment of the Phagocyte to the Pathogen  Here, receptors present on the cell surface of the phagocyte bind or adhere to the surface of the pathogen. This step is necessary for the ingestion of foreign particles. However, some bacteria can resist attachment, making it harder for the phagocytic cell to be taken into the cell and destroyed. Different types of cells express different types of receptors; some are general, while some are specific. However, depending on the cell, there are mainly four types of surface receptors that play an essential role in phagocytosis (binding). They are given below:  Opsonin Receptors: These general transmembrane receptors are present on the cell surface of phagocytes (macrophages and neutrophils) and act via specific antimicrobial proteins called opsonins . In Greek, ‘ opson ’ means to ‘prepare for eating.’  These molecules enhance phagocytosis efficiency by phagocytic cells either by activating the complement pathway or marking the antigen with a specific antibody which makes it easier to recognize by the respective receptor. The process of coating pathogens to promote phagocytosis is called opsonization.

20. Scavenger Receptors: Scavenger receptors are a general type of Pattern recognition receptors (PRRs). Thus they recognize pathogen-associated molecular patterns (PAMPs) such as peptidoglycan, teichoic acids, lipopolysaccharide, mannans, flagellin, pilin, and bacterial DNA. Macrophages widely express scavenger receptors (SRs). These receptors can bind to a diverse array of endogenous and non-self or foreign molecules. Toll-like Receptors (TLRs): These receptors get their name from a similar receptor found in fruit flies (Drosophila melanogaster) encoded by the Toll gene. They are also a type of PRR and bind to specific molecules produced by bacteria, which activates the immune response. TLRs have numerous roles. For example, they help recognize self and non-self antigens, detect invading pathogens, bridge innate and adaptive immunity, and regulate cytokine production, proliferation, and survival. Antibodies: Some immune cells produce antibodies that can identify and bind to specific antigens, thus neutralizing or destroying the foreign object. Like Toll-like receptors, antibodies are also particular in their action, i.e., a particular antibody only act against a definite antigen. This feature is called antibody specificity. Antibodies stimulate phagocytosis by coating the pathogen, making it more accessible to the phagocytes, thus playing a significant role in opsonization. Also, antibodies like IgM trigger the destruction of pathogens by stimulating the complement pathway.

21. Step 4: Ingestion of the Pathogen  After the attachment of the phagocyte to the pathogen, the cell begins to engulf the foreign particle. Then, the phagocyte starts extending the cytoplasm (pseudopods) as it surrounds the molecule to avoid the risk of membrane damage. As the cells are reasonably flexible and fluid, the pseudopods protrude outward on either side of the particle until both ends meet. Step 5: Formation of Phagosome When a pathogen or opsonin binds to a cell receptor, it triggers actin filaments within the cell. As a result, the actins get polymerized and form pseudopodia after the ingestion of the pathogen, which then surrounds the engulfed microorganism. These two protruding arms fuse, forming a vesicular structure called a phagosome. Finally, the phagosome transports the particle into the cell. Step 6: Formation of Phagolysosome Upon entering the cell, the phagosome fuses with a lysosome, becoming a phagolysosome. Lysosomes contain hydrolytic enzymes that help in the digestion of phagocytized particles. However, for phagocytes involved in immunity, unique structures called peroxisomes are produced to trap and remove toxic molecules.

22. Step 7: Destruction of the Pathogen Phagolysosomes reduce the pH of their internal environment, making them acidic. This activity serves as an effective defense mechanism against microbes and provides a suitable medium for degradative enzyme activity. As lysosomes contain the digestive enzyme called lysozyme and various antimicrobial and cytotoxic substances, they destroy the phagocytosed pathogen. The microbes are then killed either by oxygen-dependent (oxidative) or by oxygen-independent (non-oxidative) mechanisms. Some other ways of destroying pathogens are using oxygen radicals, nitric oxide, antimicrobial proteins and peptides, and binding proteins. Step 8: Elimination of Waste Materials This is the final step of phagocytosis. Once the digested contents of the phagolysosome get neutralized, it forms a residual body containing the waste products. The wastes are then discharged from the cell by exocytosis, thus completing the process.

23. THANK YOU