1、Inflammation,NANJING MEDICAL UNIVERSITY,Jennifer Lee Lyq_52245,Chapter 2,a protective response involving host cells, blood vessels, and proteins and other mediators that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original i
2、nsult, and to initiate the process of repair.,What is Inflammation?,Those who kill the microbes may also injure the normal tissues. When the reactions are too strong, prolonged or inappropriate, damage may become dominant. Related with chronic disease and cancer.,Why do we use anti-inflammatory drug
3、s sometimes?,Stimuli for Inflammation,Infection Trauma and various physical and chemical agents Tissue necrosis Foreign bodies Immune reactions,Anything that hurt cells,Recognition of Microbes, Necrotic Cells, and Foreign Substances,Phagocytes, dendritic cells and epithelial cells express receptors
4、that sense the presence of infectious pathogens and substances released from dead cells. Toll-like receptors (TLRs) Inflammasome uric acid and extracellular ATP cholesterol crystals and free fatty acids,What is going on?,Inflammation is a stereotyped response,Dilute toxins Destroy causative agents R
5、emove debris Isolate the damaged area Initiate repairing,Exudates,The components of acute and chronic inflammatory responses and their principal functions,5 cardinal signs,Aeromonas hydrophila infection following puncture with fishing hook,Cellulitis,Chronic glomerulonephritis,Types of inflammation,
6、Acute inflammation Short duration Neutrophils (PMNs) accumulation Fluid and plasma protein exudation Chronic inflammation Longer duration Accumulation of M and lymphocytes Proliferation of fibroblasts and blood vessels,Features of Acute and Chronic Inflammation,Acute Pneumonia,Chronic Pneumonia,Acut
7、e inflammation,Acute inflammation,Vascular changes vasodilation (hyperemia) increased vascular permeability (leakage) increased adhesion of leukocytes Cellular events cellular recruitment elimination the offending agent (activation),How hyperemia occurs?,Dilation of arterioles Opening up of capillar
8、ies,Transient Arterioler Constriction,Fluid and protein leakage,Increased interendothelial spaces,transudate,Exudate,mostly the venules 20-60 microns,Stasis and Margination,What increases the permeability?,Endothelial cell contraction leading to intercellular gaps in postcapillary venules Endothelia
9、l injury (necrosis or detachment) Immediate Delayed Increased transcytosis of proteins Leakage from new blood vessels,Immediate transient leakage Begins immediately; last 15 to 60 min Caused by histamine and leukotrienes, etc,Basement membrane,Endothelial cell,Intact cell junction,Gaps between cells
10、,Normal vessel,Vessel during inflammation,Hyperemia and leakage result in,Protein-rich fluid moves out (exudates and exudation) Fluid accumulation in extravascular spaces produces edema /effusion Stasis and Leuko- cytes margination,Transudates Crosses intact membrane Most clear (acellular) Caused by
11、 hydrostatic imbalance or osmotic gradients,Exudates Crosses through gaps in capillary Most cloudy (cellular) Caused by inflammation,Edema can be caused by exudates or transudates,Exudates or transudates?,Exudates or transudates?,Exudates or transudates?,Ascites A patient with liver cirrhosis,Respon
12、ses of Lymphatic Vessels,Helps drain edema fluid, leukocytes, and cell debris May transport the offending agent (especially microbes) lymphangitis lymphadenitis,lymphangitis due to Trypanosomiasis,tsetse fly,lymphadenitis due to tularemia,Groin Armpit Neck Under the jaw and chin Behind the ears On t
13、he back of the head,Common areas where the lymph nodes can be felt include:,Leukocyte Recruitment and Activation,Leukocytes are recruited and activated only when and where they are needed. Leukocytes are informed and endowed with abilities: to stop in the blood flow to diapedesis and travel toward t
14、he target to kill,Leukocyte recruitment,margination and rolling along the vessel wall firm adhesion to the endothelium transmigration between endothelial cells (diapedesis) migration in interstitial tissues toward a chemotactic stimulus (chemotaxis),chemoattractants,Chemotaxis,Chemoattractants,Solub
15、le bacterial products Complement components C5a Chemokines (IL-8, MCP-1) LTB4 (AA metabolite),Transmigration,Amoeboid movement,What type of leukocytes are recruited in different settings of inflammation?,Varies with the age of the inflammatory response the type of stimulus Viral infection-lymphocyte
16、s Hypersensitivity reactions-eosinophils,PMNs,Monocytes/macrophges,6hr,24hr,48hr,72hr,Viral encephalitis,Asthma,Leukocytes activation,Phagocytosis recognition and attachment of the particle to the ingesting leukocyte engulfment killing and degradation of the ingested material. Production of mediator
17、s Liberation of substances that destroy extracellular microbes and dead tissues,Phagocytosis,Oxygen dependent (oxidative burst) reactive oxygen species (ROS) Oxygen-independent lysosomal enzymes ,Destructive mechanisms of the leukocytes,superoxide ion hydrogen peroxide hypochlorous radical,Oxygen-in
18、dependent killing,Bactericidal permeability increasing protein (BPIP) Degrades membrane phospholipid Defensins Punches holes in bacterial membrane Lysozyme Cleave sugar chains in bacterial cell walls Also found in tears, mucus, urine,Oxygen-independent killing,Major basic protein Cytotoxic for paras
19、ites In eosinophil granule Lactoferrin Binds iron for bacteria growth Acidic pH (around 4-6) Degradative enzymes Digest bacterial components Liquefy debris,phagocyte,A long fibre,Leaked enzymes,Frustrated phagocytosis,Neutrophil extracellular traps (NETs),Leukocyte-Induced Tissue Injury,“bystander“
20、tissues Ischemia reperfusion Autoimmune diseases,Acquired Defects in Leukocyte Function,Radiation injury Cancer therapy Glucocorticoid administration Diabetes Alcoholism,Inherited Defects in Leukocyte Function,Defects in leukocyte adhesion LAD-1 LAD-2 Defects in microbicidal activity Chronic granulo
21、matous disease Defects in phagolysosome formation Chdiak-Higashi syndrome,CGD,Outcomes of acute inflammation,SARS,SARS suviving patient Difusse interstitial pulmonary fibrosis,Summary: Acute inflammation,rapidly delivers and to sites of injury the main vascular reactions are and the resulting fluid
22、accumulation is called after the endothelial cells get the signal from, they and leukocytes upregulate the expression of to facilitate the movements of leukocytes that include and ,predominate in the early inflammatory infiltrate and are later replaced by . the main jobs of leukocytes at site are an
23、d the most powerful weapons to kill is called owned by acute inflammation often cause unwanted damage because the out comes may be , or,Summary: Acute inflammation,Morphologic Patterns of Acute Inflammation,Serous inflammation Fibrinous inflammation Suppurative (purulent) inflammation and abscess fo
24、rmation Ulcer,Serous inflammation A skin blister,Herpes simplex virus infection,Skin blister,Skin blisters,pleural effusion,Fibrinous pericarditis,Fibrinous Pericarditis,Fibrinous Pericarditis,Early organization of the fibrinous exudate,adhesive pericarditis,constrictive Pericarditis,Pseudomembrane,
25、A PSEUDOMEMBRANE results when the upper portion of a mucosal surface undergoes necrosis, freeing fibrinogen from vessels that then clots along the surface,Diphtheria,Corynebacterium diphtheriae,Diphtheria,the intense intrabronchial exudate that makes up the pseudomembrane,Irregular yellow plaques of
26、 pseudomembrane (black arrow) with intervening edematous bowel mucosa (white arrow) in an 87-year-old woman.,Proctoscope,Pseudomambranous colitis,History of the patient,10 days earlier, she had been treated for right lower lobe pneumonia at another institution. She was discharged on moxifloxacin (Av
27、elox) and doxycycline (Vibramycin). She returned home, where she was recovering, but then she became weak, short of breath, and constipated. She also passed several loose stools.,Pseudomambranous colitis,47 year old patient who recently finished a course of antibiotics, now has watery diarrhea and a
28、bdominal pain.,Clostridium difficile infection,Recent history of antibiotic use Sudden leukocytosis Age and frail condition,How to diagnose? How to treat?,acute lobar pneumonia,Normal lung,acute lobar pneumonia,Pulmonary fibrosis (complication),Suppurative (purulent) inflammation,An exudate consisti
29、ng of neutrophils, necrotic cells, and edema fluid is PUS The preferred adjective to describe things with lots of pus is PURULENT. To produce pus is to SUPPURATE Pus that literally fills an important body cavity is called an EMPYEMA,Purulent meningitis,Gyrus,Sulus,Purulent meningitis,Purulent mening
30、itis,Suppurative exudates on appendix serosa,Acute appendicitis,Normal appendix,Acute appendicitis,Acute appendicitis,Acute appendicitis the lumen,Pus in the lumen of the appendix,Acute appendicitis,Normal appendix muscles,Discussion,When treated promptly, most patients recover without difficulty. I
31、f treatment is delayed, the appendix can burst, causing peritoneal infection and even death. Why?,Abscess,Pus in a confined space other than a natural body cavity Caused by seeding of pyogenic organisms into a tissue secondary infections of necrotic foci As the pus builds up pressure, abscesses may
32、find their way to a surface and rupture.,renal abscess,Liver abscess,Lung abscess,Furuncle (boil),Furuncle (boil),Furuncle (boil),carbuncle,Tooth abscess,Fistula formed from anorectal abscess,Cavity due to pulmonary abscess,acute pyelonephritis,Ulcer,an ulcer forms when necrosis has involved a body
33、surface and a portion of it is sloughed. there must be necrosis of both the epithelium and at least some of the underlying connective tissue.,Peptic ulcer,duodenal ulcers,stomach ulcers,Upper endoscopy,X-ray (barium),Peptic ulcer,Chemical mediators,Responsible for the vascular and cellular events Re
34、leased (histamine), produced (PG) or activated at the site of inflammation Derived from cells or plasma,Most act by binding to specific receptors on different target cells, others have direct enzymatic and/or toxic activities (ROS). The actions of most mediators are tightly regulated and short-lived
35、.,Chemical mediators,Cell-derived mediators,Histamin (vasoactive amines) released from mast cell causes arteriolar dilation and rapidly increases vascular permeability by Arachidonic Acid Metabolites (Eicosanoids): Prostaglandins, Leukotrienes, and Lipoxins,Arachidonic Acid Metabolites,AA is a compo
36、nent of cell membrane phospholipids (Glucocorticoids inhibit the activity of phospholipase A2 and thus the release of AA) Leukocytes, mast cells, endothelial cells, and platelets are the major sources can mediate virtually every step of inflammation,Arachidonic Acid Metabolites,Prostaglandins (PG) v
37、asodilation and potentiates edema formation contribute to the pain and fever Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase activity thus blocking eicosanoid synthesis,Arachidonic Acid Metabolites,LTB4 is produced by neutrophils and some macrophages and is a potent chemotactic
38、agent for neutrophils. Lipoxins inhibit neutrophil chemotaxis and adhesion Made by cells that have escaped the blood Platelets produce lipoxins by a transcellular biosynthetic pathway,Principal Inflammatory Actions of AA Metabolites,Other cell-derived mediators,Platelet-Activating Factor Cytokines (
39、TNF, IL-1, IL-6, chemokines ) ROS Nitric Oxide Lysosomal Enzymes of Leukocytes Neuropeptides such as substance P,The complement-derived factors,Positive vascular effects (C3a and C5a) Leukocyte activation, adhesion, and chemotaxis (C5a) Phagocytosis (C3b as a opsinin) membrane attack complex (MAC) k
40、ills,Coagulation and Kinin Systems,bradykinin causes increased vascular permeability, arteriolar dilation and pain Coagulation proteins: Activated factor XII triggers the clotting, kinin, and complement cascades and activates the fibrinolytic system.,Chronic inflammation,of prolonged duration (weeks
41、 to years) Persistent infections Immune-mediated inflammatory diseases Prolonged exposure to potentially toxic agents Conditions associated with chronic disease such as Alzheimer disease, atherosclerosis, type 2 diabetes, and some forms of cancer continuing inflammation, tissue injury, and healing,
42、proceed simultaneously,Chronic inflammation,Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells Tissue destruction, largely induced by the products of the inflammatory cells Repair, involving new vessel proliferation (angiogenesis) and fibrosis,A wound at the an
43、kle of a Japanese man who has a history of canine bite 25 years ago.,Mycetoma,Mycetoma (madura foot) Severe case,Chronic Cholecystitis,Normal gall bladder,polyps,Inflammatory polyp/pseudotumor,Colon polyp Colorectal Polyps Rectal polyp Cervical polyp Nasal polyp Bladder polyp Intestinal polyp Uterin
44、e polyp Endometrial polyp,Granulomatous Inflammation,A distinctive pattern of chronic inflammation characterized by aggregates of activated macrophages (epithelioid cells) Limited conditions to cause it: certain infections (Tuberculosis) immune-mediated (Crohn disease) inert foreign bodies unknown e
45、tiology (sarcoidosis),Tuberculosis,Tuberculosis,Tuberculosis,Tuberculosis,Syphilis Gummas,Effectively “walls off” the offending agent (not always eradicates) Tissue distruction Serious tissue fibrosis,Granuloma,Syphilis Gummas,Syphilis(Gummas),Systemic Effects of Inflammation,the acute-phase reaction Fever (pyrogens) Elevated plasma levels of acute-phase proteins C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein erythrocyte sedimentation rate (ESR) Leukocytosis (“shift to the left.” ) Mediated by TNF, IL-1, and IL-6,Thank You !,
