Raghda Al-Droubi Mariam Ababneh

Cell-Derived Inflammatory Mediators

Nitric oxide free radicalsو هوه بحد ذاته cell derived mediatorمن ال

• Short-lived • Soluble • Free radical • Different producers and different functions:

ال بنصنع فه cellاله وظائف حسب المكان ال

-CNS…affects neurotransmitter release and blood flow -in macrophages…destroy microbes

destruction of microbesاله دور ف ال free radicalلانه هوه

-by endothelial cells…vascular S.M. relaxation & vasodilation inflammationجزء من ال vasodilationلانه ال inflammationله دور مهم ف ال

Inflammation : 1-cellular action 2-blood vessel changes

NO, cont’d

• O2+NADPH+L-arginine NO

• Type II NOS • = iNOS • = inducible NO

Nitric oxide synthase (NOS)

3 isoforms

Type I NOS = nNOS = neuronal NOS

Insignificant in inflammation

Type II NOS =iNOS = inducible NOS

inflammationبنتذكر ال هونInduced by microbes

*induced in macrophage and endothelial cell due to: -IL-1 -TNF -IFN-γ -bacterial endotoxin *also present in respiratory epithelial cells, cardiac myocytes, and hepatocytes

Type III NOS = eNOS = endothelial NOS

Mainly but not exclusively in endothelial cells :بعمل

1-vasodilation 2-smooth muscle relaxation.

inflammationعن اله دخل ف ال

ال بصنعه tissueحسب ال isoformsاله NOSال *

NOSو الاكسجن و انزم NADPH بوجود L-arginineمن ال شتق *

ملاحظة ف سلادة

9رقم

غاما و لست الفا

Functions of NO

• Microbicidal (cytotoxic) in activated macrophages

• Vasodilation

• Antagonism of platelet -adhesion

-aggregation

-degranulation

بمنع تشغل و NO ال

تنشط و تجمع ال platelet.

Lysosomal enzymes of leukocytes

• Acid proteases…act only inside phagolysosome

phagolysosomeعن لازم كون جوا ال lysosomeبحطم البروتنات جوا ال

• Neutral proteases…active in extracellular locations -elastase -collagenase -cathepsin

They also cleave: -C3 C3a -C5 C5a -kininogen bradykinin-like peptides

These are called:

الانزمات ال داخل ال

lysosome ال داخل الWBCs phagocyteال على رأسهم ال

macrophageال همه ,neutrophil ف حالة ال

inflammation.

anaphylatoxin

extra cellularly ما بدها بئة حمضة بالتال ممكن تشتغل **

neutral extra cellular tracksهمه ف حالة ال neutral proteasesهدول ال تاعها و عمل متل chromatinلما الخلة ماتت و طلعت ال neutrophilشبكة الصد ال بتطلعها ال

و كمان ف انزمات طلعت لبرا و اشتغلت على هالمكروبات ال علقت , الشبكة ال علقت فها المكروبات neutral proteases)هاي الانزمات اسمها (بالشبكة

Vasodilation Increase permeability

Inhibitors of lysosomal enzymes

• Antiproteases:

-α1-antitrypsin…the major inhibitor of neutrophil elastase

-α2-macroglobulin

Its deficiency will cause:

α-1ف ال deficiencyاذا صارعندي antitrypsin ال elastase بصر حطم

عشان هك بعملل مشكلة ف tissueبال lung اسمها«emphysema » بسبب ال

destruction of the wall of the bronchiole by the elastase

α-1 antitrypsinال ما منعه ال

Neuropeptides

• Small proteins

• Substance P…the typical example

permeabilityو بتزد ال vasodilationو بتعمل ,,, nerve fibersو تفرز من ال pain signal بتنقل ال

• Transmit pain signals

• Regulate vessel tune

• Modulate vascular permeability

• Especially from nerve fibers in GIT and lung

Inflammation (4 of 5)

What will we discuss today?

• Plasma protein–derived mediators

• Anti-inflammatory mediators

• Morphologic patterns of acute inflammation

Plasma protein–derived mediators

… 3 systems:

-Complement system innate immune system لكن تواجد ال adaptive immune system جزء من ال anti body و ال antibodies بعتمد ف كثر من الاحان على ال

complement protein ف الدم و مهاجمتهم مباشرة لل microbes بجعلهم innate immune system (خط دفاع ابتدائ ) بهاجم .antibodiesال بتفرز lymphocyte لل activation المكروبات من البداة مش بصر

-Kinin system

-Coagulation system

cell derivedمو plasma proteins بروتناته بتكون **

thrombosisف حالة ال fibrin هدفه تكون ال **

Complement 3 pathways

Robbins basic pathology 9th edition

الهم محصلة واحدة 3هدول ال

C3ه تكون اش اسمه convertase

اول واحد

اكتشف و

اخر واحد

بطلع لأنه

بعتمد على anti body - anti gen complex

Each complement component needs to be cleaved (activated) by proteolysis to be able to act as enzyme that can cleave another component and so on…cascade of reactions

Each large fragment takes the name C#b

Each small fragment takes the name C#a

Large fragment is the fragment that can act as enzyme and cleave the next component in the cascade

Cascade* من التفاعلات

complement component مركبات

تحفز بعضها البعض ه ممكن تكون cascadeال

pathways 3احدى lectin, classical and

alternative.

complementاي * component بنقسم الى

a جزء صغر وb جزء

enzymaticكبر ال اله activity ف بعض

.الاحان

سلسلة من التفاعلات cascade عبارة عن **

بج انزم inactive بكون عندي بروتن

و جزء active بشتغل عله جزء منه بصر

الجزء النشط بروح بنشط جزء inactiveمنه

.cellجدد ف ال

البروتن ال تنشط بصرله **

cleavage بنقسم لقسمن

active (enzymatic activity) and inactive

)بشتغل شغل تان (

Complement, functions

• Opsonization of particles such as microbes for phagocytosis…C3b . complement systemمثلا وظائف متعددة لمكونات مختلفة من ال opsoninبعمل مثل ال

opsonization تعن تربط على سطح البكترا و بتحفز الmacrophages لتأت للخلة و تبتلعها.

• Chemotaxis…C5a and to a lesser degree: C3a and C4a

• Anaphylatoxins…C3a and C5a which affect mast cells to release histamine (vasodilation + increased vascular permeability)

• Arachidonic acid metabolism in WBCs …induced by C5a

مثل eicosanoidsنتج leukotriene,lipoxins,postaglandines,thromboxin

• Formation of membrane attack complex (MAC)

A hole formed by multiple copies of C9 in the membrane of the cell we want to destroy

Binds to complement receptor on phagocyte

Especially against Neisseria

C for Complement B - P - D

بعمل , تكون ف غشاء البكترا و ؤدي الى قتلها MACالل اشتغلوا ممكن اش نته بتكون اش اسمه pathwaysمن ال** .وقتله OSMOLARITY FOR MICROBES قناة و بدمر ال

C4b*** بصر على غشاء البكترا او الخلة مثلا اذا ال complement اشتغل غلط و ف autoimmune disease و أت عله C4bالهدف انه بج على سطح خلة و بتراكم ال MACمن جسم الانسان نفسه فال ممكن حطم خلاا

C5,C6,C7,C8,C9 (MAC ) ,

C9 اجوا مجموعة مش واحد و عملوا قناة ف الmembrane فعطلوا ال osmolarity for membrane وعملواlysis for cell .

The classical pathway of complement

Immune response ال حصل عملadaptive system ال طلع و اشتغل و طلع antibodies من الB cells (B lymphocyte) ال C3 convertaseو بتحفز مراحل تنته ب C1رتبط فها Ag-Ab complexو عملت antigenارتبطت بال antibodiesتصنع

.C3a and C3b الى C3لل cleavageرح حفز ال

• Steps:

1- Immune complexes (Ag-Ab) are formed

2- C1 is activated by binding to these complexes

3- A C3 convertase is formed

4- C3 is cleaved to C3a and C3b

antigen antibody complexesبعتمد على *

C1بحفزوا ال *

The alternative pathway of complement

*In this pathway, we need: - Bacterial polysaccharides (e.g., endotoxin) and other microbial cell wall components - Properdin factor P (a complement component)

- Factor B (a complement component) - Factor D (a complement component)

also… C3 convertase is formed

بحفز , من الجدار تبع البكترا endotoxin,ف عندنا سطح البكترا او مركب من بكترا

factor D,factorو لكن بمساعدة C3 convertaseهو بحد ذاته , مباشرة C3ال B,factorP بالتعاون مع الendotoxin او جدار البكترا بحفزوا الC3 .

The lectin pathway of complement

A plasma lectin binds to mannose residues on microbes (in the absence of antibodies)

Few steps

C3 is cleaved

Lectin بروتن برتبط بال mannose sugar سطح البكترا او على سطح على

. microbesال

تبع ذلك احداث

Lectinالجزء الثان من ال

(collagen like domain of lectin ) C3 ال بحفزوا C4 و C2بتحفز ال

بصرله complement componentكل

cleavage بنقسم الىC#a ( جزء صغر بشتغل شغل

(enzymatic activityجزء كبر ) C#bو ( ثان

To C3a and C3b by C3 CONVERTASE

Inhibitors of complement system

• C1 inhibitor C1 esterase inhibitor

…inherited deficiency of C1 inhibitor: hereditary angioedema

• Decay-accelerating factor (DAF)

…its deficiency: paroxysmal تعن على شكل نوباتattacks

nocturnal تعن لل hemoglobinuria hemolysis والglobins بتطلع بال urine

(complement-mediated lysis of RBCs) ؤدي الى هذا المرض uncontrolled ال

• Factor H

…its deficiency: -hemolytic تعن hemolysis of RBCs uremic من uremia syndrome

-macular degeneration of the eye in retina

Activation of complement

Kinins

Edema in tissues including

larynx

•Kinins حفز الvasodilation and increase vascular permeability , نستفد منه بالinflammation بدرجة .محدودة

--زاده عن اللزوم edemaسبب -–غر مضبوط و بصر شتغل زادة kininغر موجود بصر ال C1 inhibitorاذا • . suffocationممكن سبب اختناق --- edema in larynxالخطورة ف الموضوع تعمل

*factor H

hemolytic uremic syndrome هاد المرض بج بال hemolysis and renal failure عشان هك بصر عندهمuremia ارتفاع الورا بالدم لأنه الkidney ارتفاع الورا مع وجود اعراض , لما تفشل سرتفع الورا و الكراتنن بالدم

. uremia كتعرف لل

Coagulation and kinin systems

• Some molecules activated in clotting will activate multiple inflammatory responses

Of these molecules: Hageman factor (also known as factor XII of the intrinsic coagulation cascade)

- Produced by the liver - Produced inactive then

become activated at sites of endothelial injury

How will Hageman factor contribute in inflammation? …see next slide

How will Hageman factor contribute in inflammation?

**Activated Hageman factor (factor XIIa) initiates four systems that may contribute to the inflammatory response:

• The kinin system…produces vasoactive kinins

• The clotting system… -thrombin

-fibrinopeptides

-factor X

• Fibrinolytic system ال حفز factor12 و زد ال response من جدد …activation of plasmin cleavage للC3 وبحفز complement system ال هو inflammation

• Complement system

Have inflammatory properties

Thrombin

adhesion تسبب زادة ال endothelial cellsال موجود على سطح protease activated receptor برتبط على -of WBCs و بعملactivation لبعض ال molecule ال همه adhesive for WBCs .

ال همه من ال C5a and C5b اشاء تنتج عنها مثل ال inflammation , more adhesion for WBCs سهم ف ال -cleavage لل C5 جزء من ال complement و جزء من ال inflammation.

. thrombinف مركبات بتتنشط بسبب ال activation for complement ,عمل -

, fibrinل fibrinogenتحول ال fibrin ال بصر فها تراكم لل coagulation system من المراحل النهائة ف **-و برضه ف , طولة cascade الهدف النهائ لكن fibrinال ف الاخر بتكون هو عبارة عن clot or coagulantال

cascade ثانة رح تشتغل موازة الها و تبدا معها ه fibrinolytic system تعمل control عشان الموضوع ما زد عن حده

.fibrin تراكم و ف اشاء بتحلل ال fibrin اذا ال ---

Factor X

. inflammation chemotaxis and vascular permeability سهم ف ال

-fibrinopeptides بزد الchemotaxis و بزد ال vascular permeability .

Fibrinolytic system

. cleavage for C3 مثلا بعمل complement من خلال تحفز ال inflammation رح سهم ف ال

The clotting system • Factor Xa… -increased vascular permeability

-chemotaxis

• Thrombin…- Binds to “protease-activated receptors” on many cell

types…on endothelial cell: more adhesion to WBCs

- Generates fibrinopeptides: -increased vascular permeability

-chemotaxis

- Cleaves C5 (complement activation)

• Fibrinolytic system: …this system is activated concurrently whenever clotting is initiated

-fibrin degradation products…vascular permeability -Plasmin…-cleaves C3 -also activates Hageman…augmentation of responses