Ahmad Shihada Silmi Msc, FIBMS IUG Medical Lab. sciences Dept Kinin system Ahmad Shihada Silmi Msc, FIBMS IUG Medical Lab. sciences Dept

Introduction All the following physiological processes are activated in a cascade-like manner: Complement Kinin generation Blood coagulation Fibrinolytic system They interact with one another and with various cell membrane proteins.

The kinin interaction System Pre-Kallikrein Kallikrein Kininogen HMWK, LMWK Kinin e.g. Bradykinin F XIIa F XII Surface Fibrinolytic Pathway Plasminogen Plasmin Complement Activation Clotting Cascade (intrinsic pathway) Effects vascular smooth muscle relaxation Increased permeability of blood vessels  Oedema Pain Interaction with clotting cascade Interaction with fibrinolytic cascade Interaction with complement cascade

Kinin system It's the second important-forming system. It's product is Bradykinin. Bradykinin functions: Increase vascular permeability. Vasodilatation. Hypotension. Pain. Contraction of smooth muscles. Activation of arachidonic acid. Blood pressure homeostasis and renal function.

Bradykinin Receptors B1 & B2 receptors that present on the membrane of many cell types including: Vessel endothelial cells Smooth muscle Nerve cells Synovial lining cells Bradykinin interaction with receptor causes the release of a variety of cytokines that alter cellular function.

Proteins of the kinin cascade Hagaman factor. Factor XI. Prekallikrein. High-molecular-weight kininogen.

Physiology of kinin system Factor XI circulate as a complex with HMWK in a molar ratio of 2:1. Prekallikrein circulate in a complex with HMWK in a molar ratio of 1:1. Hagaman factor circulates as an uncomplexed single-chain protein.

Steps in kinin activation On interaction with a negatively charged surface such as: In-vitro: glass (experimently) In-vivo: lipid A of gram-negative bacterial endotoxin. hageman is cleaved & activated (αHFa). αHFa can activate more Hageman factor to produce more αHFa.

Steps in kinin activation αHFa can interact with XI-HMWH and activate XI to factor XIa activate the intrinsic coagulation cascade. αHFa can also interact with HMWK-prekallikrein complex and activate PK to K. To facilitate activation of PK and XI, HMWK is bound to the surface near Hageman factor (XII)

Steps in kinin activation Active Kallikrein cleave HMWKto release Bradykinin. Bradykinin has a short half-life and attacked by carboxypeptidase N enzyme to form des-arg-bradykinin which has few vascular effects. Des-arg-bradykinin is cleaved by angiotensin-converting enzyme (ACE) to form inactive peptide.

Plasma inhibitors of kinin generation The principal inhibitors are: C1 inhibitor (major inhibitor for K & XII). α2 macroglobulin (2nd for K & XII). α1 proteinase (major inhibitor for Xia).

Low molecular -weight Kininogen Tissue kallikrein can activate LMWK to lysylbradykinin (kallidein) which undergoes the same degredation pathway as does bradykinin.

Functions of kinin in disease Both bradykinin & lysylbradykinin contribute with the following diseases: Rhinitis Asthma Pancreatitis Synovitis Hereditary angioedema