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Principle of Inflammation and Infection

Natapol Supanatsetakul MD, PhD.Dept. of Pathology and Forensic MedicineFaculty of Medicine, Naresuan University

17 มิถุนายน พ.ศ. 2554

TOPICS

Inflammation– Acute inflammation– Chronic inflammation

Tissue repair

Principle of Infectious Disease

INFLAMMATION

Complex reactions to injurious agent that consists of – Vascular responses– Migration and activation of leukocytes– Systemic responses

Closely intertwined with the process of repair

5 cardinal signs: pain, swelling, erythema, heat and loss of function

Inflammation is fundamentally a protective response, but may be potentially harmful

Inflammation consists of two components–Vascular reaction–Cellular reaction

Vascular and cellular reactions are mediated by chemical factors, derived from plasma proteins or cells (Cytokines) and are produced in response to or activated by the stimuli

Inflammation is divided into– Acute inflammation– Chronic inflammation

ACUTE INFLAMMATION

Rapid response to an injurious agentthat serves to deliver mediators of host defense (leukocytes and plasma proteins) to the site of injury

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Three majors components:

1. Alterations on vascular caliber that lead to an increase in blood flow

2. Structural change that permit plasma protein (fibrin, complement) and leukocytes to leave the circulation

3. Emigration of the leukocytes from the microcirculation to the stimulated site

Stimuli for Acute inflammation

Infections and microbial toxinsTraumaPhysical and chemical agentsTissue necrosisForeign bodiesImmune reactions

Vascular ChangesChanges in vascular flow and caliber– Vasodilation – Earliest manifestation of acute inflammation– Stasis increased blood viscosity – Quickly followed by increased vascular

permeability

Increased vascular permeability– Hallmark of acute inflammation– Protein and fluid leakage from the lumen

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Exudate : extravascular fluid that has high protein concentration

Transudate : extravascular fluid that has low protein concentration

Pus or purulent exudate : leukocytes-rich exudate with cellular debris

Cellular Events

Margination Rolling AdhesionTransmigration (diapedesis)Migration chemotaxis

CHEMICAL MEDIATORS OF INFLAMMATION

Mediators or originate either from plasma from cellsThe production is triggers by microbial products or by host proteins, other chemical mediatorsMediators perform activity by binding their specific receptorsOne mediator can stimulate the release of other mediatorsMediators have different effects on different cell typesMost mediators are short-lived

Chemical mediators

Vasoactive amines: HistaminePlasma proteins: complement system, kinin system, clotting and fibrinolytic systemArachidonic acid metabolites: prostaglandins, leukotrienes, thromboxanesCytokines and chemokines: Interleukin-1(IL-1), Tumor necrotic factor (TNF)Nitric oxide

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Effects of Chemical mediators

Pain: Prostaglandin, bradykininIncreased vascular permeability, edemaVasodilation: histamine, NO Fever, acute phase symptoms: IL-1, TNFTissue damageChemotaxis, leukocyte recruitment and activation

OUTCOME OF ACUTE INFLAMMATION

Complete resolution

Healing by connective tissue replacement(Fibrosis, scar)

Chronic inflammation

MORPHOLOGIC PATTERN OF ACUTE INFLAMMATION

Serous inflammation– Burn– Inflammation in the body cavity

Fibrinous inflammation– Severe injury, results in greater vascular

permeability– Leakage of fibrinogen (plasma protein)

Suppurative or purulent inflammation– Inflammation with pus or purulent exudate

formation– Acute appendicitis– Acute meningitis– Abscess : localized collections of purulent

inflammatory tissue– Fibrinopurulent inflammation

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Ulcers – Local defect or excavation of the surface of

an organ or tissue – Most common encounter in

Oral mucosaSubcutaneous tissue

https://www.bcbsri.com/BCBSRIWeb/images/image_popup/r7_ulcers.jpg

https://www.vivature.com/pages/xhtml/medicalLibrary/images/skin_ulcer_minor.jpg

http://www.visualdxhealth.com/images/dx/webAdult/stasisUlcerVenousUlcer_45074_med.jpg

Skin ulcerCHRONIC INFLAMMATION

Inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously.

Cause of chronic inflammation

Persistent infection

Prolonged exposure to potentially toxic agents, either exogenous or endogenous

Autoimmunity

Morphologic features

Infiltration with mononuclear cells, including macrophages, lymphocytes and plasma cells (Acute inflammation = Neutrophil)

Tissue destruction

Healing by connective tissue replacement of damaged tissue (fibrosis, scar)

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http://www.chronicprostatitis.com/images/neutrophil.jpghttp://faculty.une.edu/com/abell/histo/neutrophil.jpghttp://medicineworld.org/images/blogs/1-2007/programmed-cell-death-441.jpg

Neutrophil

Macrophage

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http://education.vetmed.vt.edu/curriculum/VM8054/Labs/Lab5/IMAGES/Macrophage%20WITH%20LABEL%2096%20DPI.JPG

T lymphocyte

http://202.129.54.82/faculty/web_bed/apichat/cardio-vascular/picture/lymphocyte.jpg

http://www.daviddarling.info/images/T-lymphocyte.jpg

http://www.sciencemuseum.org.uk/on-line/lifecycle/images/1-2-6-6-2-3-0-0-0-0-0.jpg

B cell and plasma cell

http://pathology.mc.duke.edu/research/Histo_course/plasmacell.jpg

http://www.uab.es/uabdivulga/img/fagocitos3.gif

https://www.med.illinois.edu/m34/clerkships/surgery/student/other/path/slides/Cholelithiasis%20&%20Chronic%20Cholecystitis.jpg

http://www.pathology.vcu.edu/education/gi/MacronodularCirrhosisHepatitisC.jpg

Chronic cholecystitiswith gall stones

Chronic hepatitis with progressive to cirrhosis

TOPICS

Inflammation– Acute inflammation– Chronic inflammation

Tissue repair

Principle of Infectious Disease

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REPAIR

Maintenance of normal structure and function and survival of the organism

Regeneration

Healing: scar formation and fibrosis

Regeneration : growth of cells and tissue to replace lost structure– Tissue with high proliferative activity :

hematopoietic tissue (bone marrow), epithelium (epidermis, GI)

– Intact connective scaffold

Healing : restore original structures involving collagen deposition and scar formation– Wound, inflammation, necrosis

TISSUE-PROLIFERATIVE ACTIVITY

Labile tissue (continuous dividing tissue)– Epithelium– Hematopoietic cells in bone marrow

Stable tissue (quiescent tissue)– Liver– Kidney – Mesenchymal tissue : fibroblasts, smooth

musclePermanent tissue (nondividing tissue)– Brain – Cardiac and striated muscle

HEALING, SCAR FORMATION AND FIBROSIS

Induction of an inflammatory processes

Proliferation and migration of parenchymal and connective tissue cells

Formation of new blood vessels and granulation tissue

Hallmark of healing : proliferation of fibroblasts and endothelial cells to form granulation tissue Granulation tissue

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CUTANEOUS WOUND HEALING

Inflammatory processGranulation formation and re-epithelializationExtracellular matrix deposition, wound contracture and tissue remodeling

First intention woundSecond intention wound

HEALING BY FIRST INTENTION

24 hr : migration of neutrophils, re-epithelialization

Day 3 : migration of macrophages, granulation tissue formation, collagen synthesis

Day 5 : more granulation tissue formation and collagen synthesis, bridge in the incision, epidermis recover normal thickness

Week 2 : continue proliferation of fibroblasts and collagen deposition

1 month : complete scar formation

HEALING OF SECOND INTENTIONMore inflammatory processMore granulation tissue formationMore wound contracture : myofibroblastsThinning of new epithelium

WOUND STRENGTH1 week : 10%3 months : 70-80%

COMPLICATION IN CUTANEOUS WOUND HEALING

Inadequate formation of granulation tissue and scar formation

Excessive formation of the repair components– Hypertrophic scar – Keloid

Formation of contracture

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http://img.medscape.com/pi/emed/ckb/dermatology/1048885-1128404-2359.jpg

Hypertrophic scar Keloid

Scar Contracture

Principle of Infection

Overview and History of Infectious diseaseClassificationPathogenesis of Infectious DiseasePathologyClinical Evaluation

Overview and History

Infectious disease หมายถึง โรคที่เกดิจากสิ่งมีชีวิตที่สามารถกอโรคได (Pathogen)

In the year 1796, Jenner คนพบวามี cross reactive immunity ระหวาง Cowpox และ Small pox เปนจุดเริ่มตนการพัฒนาวัคซีนปองกันโรคฝดาษ (Small pox)

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Edward Jenner

On 14th May 1796, Edward Jenner vaccinated an 8 year old boy, James Phipps,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 of vaccination which healed in 2 weeks.On 1st July 1796, Jenner challenged the boy by deliberately inoculating him withmaterial from a real case of smallpox!

History:

- Louis Pasteur and Robert Koch; establishing the microbiologic etiology of infectious disease.- Pasteur;

* proving that microorganisms can cause disease

* created first live-attenuated vaccines; rabies vaccine for human in 1885.

Classification

According to PathogenicityAccording to Site of Multiplication According to Structure

Classification according to Pathogenicity

- High virulence- Low virulence; opportunistic infection

Classification according to Site of Multiplication

- Obligate intracellular organisms- Facultative intracellular organism- Extracellular organisms

Obligate Intracellular Organisms

- เจริญเติบโตและแบงตัวใน host cell เทานั้น- Prions- All viruses- All rickettsiae- All chlamydiae- Some protozoa

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Facultative Intracellular Organisms

- แบงตัวไดทัง้ใน และนอก host cell- Mycobacteria; M. tuberculosis- Brucella spp.- Actinomyces- Klebsiella rhinoscleromatis- Francisella tularensis- Pseudomonas mallei and P. pseudomallei

Fungi;- Coccidioides immitis- Histoplasma capsulatum- Cryptococcus neoforman- Blastomyces dermatidis- Paracoccidioides brasilliensis- Sporothrix schenski

Some protozoa

Extracellular Organisms

- แบงตัวนอก host cell เทานั้น- Mycoplasma- All bacteria except facultative intracellular organisms- Fungi; Candida albicans, Aspergillus spp, Mucor spp.- Some protozoa except Trypanosoma spp., Plasmodium spp., Toxoplasma spp.- All metazoa

Classification according to Structure

- Prion - Fungi- Viruses - Protozoa, metazoa- Bacteria - Ectoparasite- Rickettsia, chlamydia, mycoplasma

Prions:- 27 kD nucleic acid-free prion- are apparently composed of abnormal

forms of host protein; prion protein- these agents cause transmissible

spongioform encephalopathies; kuru, CJD, bovine spongioform encephalopathy (mad cow)

Prion disease

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Viruses:- obligate intracellular parasites that

depend on the host cell’s metabolic machinery for their replication.

- consists of a nucleic acid genome surrounded by a protein coat (capsid)

- classified by their nucleic acid genome; DNA or RNA

Bacteria:- are prokaryotes, have a cell

membrane but lack membrane-bound nuclei and other membrane-enclosed organelles.

- gram positive and gram negative- most bacteria synthesize their own

DNA, RNA, and proteins, but they depend on the host for favorable growth conditions.

http://moms.wwfx.com/part1/bugtypes1.gif

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Chlamydiae, Rickettsiae, Mycoplasma:

- divide by binary fission but lack certain structures or metabolic capabilities.

Mycoplasma lack a cell wallChlamydia cannot synthesize ATPChlamydia and Rickettsiae are obligate

intracellular organisms.

Fungi:

- eukaryotes- grow either budding yeast and hyphae

(septate and non-septate)- some of the most important

pathogenic fungi exhibit “Thermal dimorphism”:hyphal forms at room temperature but

yeast forms at body temperature

- Tinea; Athlete’s foot- Sporotrichosis; subcutaneous infection- Candida, Aspergillus, Mucor; systemic fungal infection in immunocompromisedhost

Protozoa:- single-celled eukaryotes- replicate intracellularly

(Plasmodium in RBC, Leishmania in macrophages) or extracellularly in urogenital 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 blood-sucking insects.

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Helminths:

- multicellular organisms- complex life cycles- sexual reproduction in definitive host,

asexual multiplication in intermediate host

Ectoparasites

- are arthropods (e.g., lice, ticks, bedbugs, fleas) that attach to and live on the skin.

- may be vectors for other pathogens (e.g., Lyme disease spirochetes transmitted by ticks).

Pathogenesis of Infectious Disease

Host factors– General factor– Internal factor

Pathogenic organism factors

Host factors:1. General factors: socioeconomic status, behavior pattern, occupation

2. Internal factors: Natural defense mechanism; skin and normal flora, respiratory tract and mucociliary mechanism, HCl production in stomach, or normal flushing action of urine

Internal factors: Inflammation; acute inflammation, phagocytosis, complement, and production of interferon

Internal factors: The immune response; HMI and CMI

HMI: Ag & Ab (B-cell)CMI: T- cell, macrophages

Organism factors:1. Route of entry

2. Mode of transmission; congenital transfer (Rubella, CMV, HIV, HSV), directly contact, food and water, airborne, animal, sexual transmission

3. Spread and Dissemination; localized and disseminated infection

- viremia, bacteremia, fungemia

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- septicemia: invasion of the bloodstream by virulent microorganisms from a focus of infection that is accompanied by fever, chills, tachycardia, hypotension

4. Number of organism-numerous low virulent organism can cause severe disease

5. Pathogenicity of organism; - ability to invade tissue; S.pyogenasehyaluronidase breakdown ground substance

- toxin production; C. botulinum neurotoxin

- multiplication- resistance to host defense mechanism - ability to cause necrosis- enzyme release; anthrax enzyme vasculitis ischemia

How microorganisms cause disease:

Infectious agents establish infection and damage tissues in 3 ways:

1. They can contact or enter host cells and directly cause death

2. They may release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis

3. They can induce host cellular responsesthat, although directed against the invader, cause additional tissue damage, usually by immune-mediated mechanisms. Immune are necessary to overcome the infection but at the same time may directly contribute to tissue damage.

Clinical Evaluation

Clinical historyPhysical examinationLaboratory investigation

1. Clinical history- Prevalence of infectious disease

Community acquired infectionHospital acquired infection

(Nosocomial infection)- Assessment of immune status- Exposure to animals- Travel history

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2. Physical examinationorgan-system general physical exam

3. Investigation- Microbiological tests (smear, culture)- Immunological tests (antibody titer)- Histological examination of tissue specimens- Immunohistochemistry, PCR, DNA probe, DNA microarray

Outcome of Infection

Acute inflammation– Suppurative inflammation (purulent inflammation)

Complete resolution without sequelae

Healing by connective tissue replacement(Fibrosis, scar)

Chronic infection and chronic inflammation

References

สุภรณ พงศะบุตร, บรรณาธิการ, “ตําราพยาธิวิทยาทั่วไป.”, ภาควิชาพยาธิวิทยาและนิติเวชศาสตร, โกลบอลพริ้นท, 2551, หนา 41-89, 93-118.

Kumar V., Cotran R.S., Robbins S.L., “Robbins Basic Pathology, 7th edition.” Saunders, 2003, p.33-78, 307-322.