Principle of Inflammation and Infection - Faculty of Medicine

Principle ofInflammationand InfectionTOPICS• Inflammation– Acute inflammation– Chronic inflammation• Tissue repairNatapol Supanatsetakul MD, PhD.Dept. of Pathology and Forensic MedicineFaculty of Medicine, Naresuan University• Principle of Infectious Disease17 มิถุนายน พ.ศ. 2554INFLAMMATION• Complex reactions to injurious agentthat consists of– Vascular responses– Migration and activation of leukocytes–Systemic responses• Closely intertwined with the process ofrepair• 5 cardinal signs: pain, swelling, erythema,heat and loss of function• Inflammation is fundamentally a protectiveresponse, but may be potentially harmful• Inflammation consists of two components– Vascular reaction– Cellular reaction• Vascular and cellular reactions are mediatedby chemical factors, derived from plasmaproteins or cells (Cytokines) and areproduced in response to or activated by thestimuli• Inflammation is divided into– Acute inflammation– Chronic inflammationACUTE INFLAMMATIONRapid response to an injurious agentthat serves to deliver mediators of hostdefense (leukocytes and plasma proteins)to the site of injury1

Three majors components:1. Alterations on vascular caliber thatlead to an increase in blood flow2. Structural change that permit plasmaprotein (fibrin, complement) andleukocytes to leave the circulation3. Emigration of the leukocytes from themicrocirculation to the stimulated siteStimuli for Acute inflammation• Infections and microbial toxins• Trauma• Physical and chemical agents• Tissue necrosis• Foreign bodies• Immune reactionsVascular Changes• Changes in vascular flow and caliber– Vasodilation– Earliest manifestation of acute inflammation– Stasis increased blood viscosity– Quickly followed by increased vascularpermeability• Increased vascular permeability– Hallmark of acute inflammation– Protein and fluid leakage from the lumen2

Cellular Events• Exudate : extravascular fluid that hashigh protein concentration• Transudate : extravascular fluid thathas low protein concentration• Pus or purulent exudate : leukocytesrichexudate with cellular debris• Margination• Rolling• Adhesion• Transmigration (diapedesis)• Migration chemotaxisCHEMICAL MEDIATORS OFINFLAMMATION• Mediators or originate either from plasma from cells• The production is triggers by microbial products orby host proteins, other chemical mediators• Mediators perform activity by binding their specificreceptors• One mediator can stimulate the release of othermediators• Mediators have different effects on different celltypes• Most mediators are short-livedChemical mediators• Vasoactive amines: Histamine• Plasma proteins: complement system,kinin system, clotting and fibrinolytic system• Arachidonic acid metabolites: prostaglandins,leukotrienes, thromboxanes• Cytokines and chemokines: Interleukin-1(IL-1),Tumor necrotic factor (TNF)• Nitric oxide3

Effects of Chemical mediators• Pain: Prostaglandin, bradykinin• Increased vascular permeability, edema• Vasodilation: histamine, NO• Fever, acute phase symptoms: IL-1, TNF• Tissue damage• Chemotaxis, leukocyte recruitment andactivationOUTCOME OF ACUTEINFLAMMATION• Complete resolution• Healing by connective tissue replacement(Fibrosis, scar)• Chronic inflammationMORPHOLOGIC PATTERN OFACUTE INFLAMMATION• Serous inflammation– Burn– Inflammation in the body cavity• Fibrinous inflammation– Severe injury, results in greater vascularpermeability– Leakage of fibrinogen (plasma protein)• Suppurative or purulent inflammation– Inflammation with pus or purulent exudateformation– Acute appendicitis– Acute meningitis– Abscess : localized collections of purulentinflammatory tissue– Fibrinopurulent inflammation4

• Ulcers– Local defect or excavation of the surface ofan organ or tissue– Most common encounter in• Oral mucosa• Subcutaneous tissuehttps://www.bcbsri.com/BCBSRIWeb/images/image_popup/r7_ulcers.jpgSkin ulcerCHRONIC INFLAMMATIONInflammation of prolonged duration(weeks or months) in which active inflammation,tissue destruction, and attempts at repair areproceeding simultaneously.https://www.vivature.com/pages/xhtml/medicalLibrary/images/skin_ulcer_minor.jpghttp://www.visualdxhealth.com/images/dx/webAdult/stasisUlcerVenousUlcer_45074_med.jpgCause of chronic inflammation• Persistent infection• Prolonged exposure to potentially toxicagents, either exogenous or endogenous• AutoimmunityMorphologic features• Infiltration with mononuclear cells, includingmacrophages, lymphocytes and plasma cells(Acute inflammation = Neutrophil)• Tissue destruction• Healing by connective tissue replacement ofdamaged tissue (fibrosis, scar)5

Macrophagehttp://www.aplastic-anaemia-myelodysplasia-glossary.co.uk/i/c/1_monocyte.jpghttp://education.vetmed.vt.edu/curriculum/VM8054/Labs/Lab5/IMAGES/Macrophage%20WITH%20LABEL%2096%20DPI.JPGNeutrophilhttp://medicineworld.org/images/blogs/1-2007/programmed-cell-death-441.jpghttp://www.chronicprostatitis.com/images/neutrophil.jpghttp://faculty.une.edu/com/abell/histo/neutrophil.jpghttp://education.vetmed.vt.edu/curriculum/VM8054/Labs/Lab5/IMAGES/MACROPHAGE%20IN%20SITU%20copy.JPGT lymphocyteB cell and plasma cellhttp://www.daviddarling.info/images/T-lymphocyte.jpghttp://www.uab.es/uabdivulga/img/fagocitos3.gifhttp://202.129.54.82/faculty/web_bed/apichat/cardio-vascular/picture/lymphocyte.jpghttp://www.sciencemuseum.org.uk/on-line/lifecycle/images/1-2-6-6-2-3-0-0-0-0-0.jpghttp://pathology.mc.duke.edu/research/Histo_course/plasmacell.jpghttps://www.med.illinois.edu/m34/clerkships/surgery/student/other/path/slides/Cholelithiasis%20&%20Chronic%20Cholecystitis.jpgChronic cholecystitiswith gall stonesTOPICS• Inflammation– Acute inflammation– Chronic inflammation• Tissue repair• Principle of Infectious DiseaseChronic hepatitiswith progressive to cirrhosishttp://www.pathology.vcu.edu/education/gi/MacronodularCirrhosisHepatitisC.jpg6

REPAIR• Maintenance of normal structure andfunction and survival of the organism• Regeneration• Healing: scar formation and fibrosis• Regeneration : growth of cells and tissue toreplace lost structure– Tissue with high proliferative activity :hematopoietic tissue (bone marrow),epithelium (epidermis, GI)– Intact connective scaffold• Healing : restore original structuresinvolving collagen deposition and scarformation– Wound, inflammation, necrosisTISSUE-PROLIFERATIVE ACTIVITY• Labile tissue (continuous dividing tissue)–Epithelium– Hematopoietic cells in bone marrow• Stable tissue (quiescent tissue)–Liver–Kidney– Mesenchymal tissue : fibroblasts, smoothmuscle• Permanent tissue (nondividing tissue)– Brain– Cardiac and striated muscleHEALING, SCAR FORMATIONAND FIBROSIS• Induction of an inflammatory processes• Proliferation and migration of parenchymal andconnective tissue cells• Formation of new blood vessels and granulationtissue• Hallmark of healing : proliferation of fibroblastsand endothelial cells to form granulation tissueGranulation tissue7

CUTANEOUS WOUNDHEALING• Inflammatory process• Granulation formation and re-epithelialization• Extracellular matrix deposition, woundcontracture and tissue remodeling• First intention wound• Second intention woundHEALING BY FIRST INTENTION• 24 hr : migration of neutrophils, reepithelialization• Day 3 : migration of macrophages,granulation tissue formation, collagensynthesis• Day 5 : more granulation tissueformation and collagen synthesis,bridge in the incision, epidermis recovernormal thickness• Week 2 : continue proliferation offibroblasts and collagen deposition• 1 month : complete scar formationHEALING OF SECOND INTENTION• More inflammatory process• More granulation tissue formation• More wound contracture : myofibroblasts• Thinning of new epitheliumWOUND STRENGTH• 1 week : 10%• 3 months : 70-80%COMPLICATION IN CUTANEOUSWOUND HEALING• Inadequate formation of granulationtissue and scar formation• Excessive formation of the repaircomponents– Hypertrophic scar–Keloid• Formation of contracture8

Hypertrophic scarhttp://img.medscape.com/pi/emed/ckb/dermatology/1048885-1128404-2359.jpgKeloidScar ContracturePrinciple of Infection• Overview and History of Infectious disease• Classification• Pathogenesis of Infectious Disease• Pathology• Clinical EvaluationOverview and History• Infectious disease หมายถึง โรคที่เกิดจากสิ่งมีชีวิตที่สามารถกอโรคได (Pathogen)• In the year 1796, Jenner คนพบวามี crossreactive immunity ระหวาง Cowpox และSmall pox เปนจุดเริ่มตนการพัฒนาวัคซีนปองกันโรคฝดาษ (Small pox)9

History:Edward JennerOn 14th May 1796, Edward Jenner vaccinatedan8yearoldboy,JamesPhipps,with material from a cowpox lesion on the hand of a milkmaid, Sarah Nelmes.James, who had never had smallpox , developed a small lesion at the site ofvaccination which healed in 2 weeks.On 1st July 1796, Jenner challenged the boy by deliberately inoculating him withmaterial from a real case of smallpox!- Louis Pasteur and Robert Koch;establishing the microbiologic etiology ofinfectious disease.- Pasteur;* proving that microorganisms cancause disease* created first live-attenuated vaccines;rabies vaccine for human in 1885.ClassificationClassification according to Pathogenicity• According to Pathogenicity• According to Site of Multiplication• According to Structure- High virulence- Low virulence; opportunistic infectionClassification according to Site ofMultiplication- Obligate intracellular organisms- Facultative intracellular organism- Extracellular organismsObligate Intracellular Organisms- เจริญเติบโตและแบงตัวใน host cell เทานั้น-Prions- All viruses- All rickettsiae- All chlamydiae- Some protozoa10

Facultative Intracellular Organisms- แบงตัวไดทั้งใน และนอก host cell- Mycobacteria; M. tuberculosis- Brucella spp.- Actinomyces- Klebsiella rhinoscleromatis- Francisella tularensis- Pseudomonas mallei and P. pseudomalleiFungi;- Coccidioides immitis- Histoplasma capsulatum- Cryptococcus neoforman- Blastomyces dermatidis- Paracoccidioides brasilliensis- Sporothrix schenskiSome protozoaExtracellular Organisms- แบงตัวนอก host cell เทานั้น-Mycoplasma- All bacteria except facultative intracellularorganisms- Fungi; Candida albicans, Aspergillus spp,Mucor spp.- Some protozoa except Trypanosoma spp.,Plasmodium spp., Toxoplasma spp.- All metazoaClassification according to Structure-Prion-Fungi-Viruses -Protozoa, metazoa- Bacteria - Ectoparasite- Rickettsia, chlamydia, mycoplasmaPrions:- 27 kD nucleic acid-free prion- are apparently composed of abnormalforms of host protein; prion protein- these agents cause transmissiblespongioform encephalopathies; kuru, CJD,bovine spongioform encephalopathy (madcow)Prion disease11

Viruses:- obligate intracellular parasites thatdepend on the host cell’s metabolicmachinery for their replication.- consists of a nucleic acid genomesurrounded by aprotein coat (capsid)- classified by theirnucleic acid genome;DNA or RNABacteria:- are prokaryotes, have a cellmembrane but lack membrane-boundnuclei and other membrane-enclosedorganelles.- gram positive and gram negative- most bacteria synthesize their ownDNA, RNA, and proteins, but they dependon the host for favorable growthconditions.http://moms.wwfx.com/part1/bugtypes1.gif12

Chlamydiae, Rickettsiae,Mycoplasma:- divide by binary fission but lackcertain structures or metabolic capabilities.Mycoplasma lack a cell wallChlamydia cannot synthesize ATPChlamydia and Rickettsiae are obligateintracellular organisms.Fungi:- eukaryotes- grow either budding yeast and hyphae(septate and non-septate)- some of the most importantpathogenic fungi exhibit“Thermal dimorphism”:hyphal forms at room temperature butyeast forms at body temperature- Tinea; Athlete’s foot- Sporotrichosis; subcutaneous infection- Candida, Aspergillus, Mucor; systemicfungal infection in immunocompromisedhostProtozoa:- single-celled eukaryotes- replicate intracellularly(Plasmodium in RBC, Leishmania inmacrophages) or extracellularly inurogenital system, intestine, or blood.- e.g. Trichomonas vaginalis,Entamoeba histolytica, Giardia lambia,Toxoplasma gondii- Intestinal protozoa (e.g.,Entamoeba histolytica and Giardialamblia) are infective when swallowed.- Blood-borne protozoa (e.g.,Plasmodium species and Leishmaniaspecies) are transmitted by bloodsuckinginsects.13

EctoparasitesHelminths:- multicellular organisms- complex life cycles- sexual reproduction in definitive host,asexual multiplication in intermediate host- are arthropods (e.g., lice, ticks,bedbugs, fleas) that attach to and liveon the skin.- may be vectors for other pathogens(e.g., Lyme disease spirochetestransmitted by ticks).Pathogenesis of Infectious Disease• Host factors–General factor– Internal factor• Pathogenic organism factorsHost factors:1. General factors: socioeconomic status,behavior pattern, occupation2. Internal factors: Natural defensemechanism; skin and normal flora,respiratory tract and mucociliary mechanism,HCl production in stomach, or normal flushingaction of urineInternal factors: Inflammation; acuteinflammation, phagocytosis, complement,and production of interferonInternal factors: The immune response;HMI and CMIHMI: Ag & Ab (B-cell)CMI: T- cell, macrophagesOrganism factors:1. Route of entry2. Mode of transmission; congenitaltransfer (Rubella, CMV, HIV, HSV), directlycontact, food and water, airborne, animal,sexual transmission3. Spread and Dissemination; localizedand disseminated infection- viremia, bacteremia, fungemia14

- septicemia: invasion of the bloodstreamby virulent microorganisms from a focus ofinfection that is accompanied by fever,chills, tachycardia, hypotension4. Number of organism-numerous low virulent organism cancause severe disease5. Pathogenicity of organism;- ability to invade tissue; S.pyogenase hyaluronidase breakdown ground substance- toxin production; C. botulinum neurotoxin- multiplication- resistance to host defense mechanism- ability to cause necrosis- enzyme release; anthrax enzyme vasculitis ischemiaHow microorganisms cause disease:Infectious agents establish infectionand damage tissues in 3 ways:1. They can contact or enter host cells anddirectly cause death2. They may release toxins that kill cells ata distance, release enzymes that degradetissue components, or damage bloodvessels and cause ischemic necrosis3. They can induce host cellular responsesthat, although directed against theinvader, cause additional tissue damage,usually by immune-mediated mechanisms.Immune are necessary to overcome theinfection but at the same time maydirectly contribute to tissue damage.Clinical Evaluation• Clinical history• Physical examination• Laboratory investigation1. Clinical history- Prevalence of infectious diseaseCommunity acquired infectionHospital acquired infection(Nosocomial infection)- Assessment of immune status- Exposure to animals-Travel history15

2. Physical examinationorgan-system general physical exam3. Investigation- Microbiological tests (smear, culture)- Immunological tests (antibody titer)- Histological examination of tissue specimens- Immunohistochemistry, PCR, DNA probe,DNA microarrayOutcome of Infection• Acute inflammation– Suppurative inflammation (purulent inflammation)• Complete resolution without sequelae• Healing by connective tissue replacement(Fibrosis, scar)References• สุภรณ พงศะบุตร, บรรณาธิการ, “ตําราพยาธิวิทยาทั่วไป.”,ภาควิชาพยาธิวิทยาและนิติเวชศาสตร, โกลบอลพริ้นท, 2551, หนา41-89, 93-118.• Kumar V., Cotran R.S., Robbins S.L., “Robbins Basic Pathology,7 th edition.” Saunders, 2003, p.33-78, 307-322.• Chronic infection and chronic inflammation16