Endotoxin shock is initiated by -
Ans. is 'd' i.e., Cytokines action Septic shock Septic shock is the condition where shock is caused by infection. Currently, septic shock is most frequently triggered by gram positive bacterial infections, followed by gram? nagative bacteria and fungi. Hence, the older synonym of "endotoxic shock" is not appropriate. - Robbin's 8th/e 130. Pathogenesis of septic shock Septic shock is caused by gram positive and gram negative bacteria. The microbial triggers for septic shock are. i) Gram negative bacteria : - Lipopolysaccharide (endotoxin). Gram positive bacteria : - Lipoteichoic acid, cell wall muramyl peptide, Superantigens (Staphylococal TSST, Streptococcal pyrogenic exotoxin). The initial event caused by all these trigers is the release of cytokines; However, mechanism is different : ? i) Gram negative bacteria (Endotoxic shock) o Lipopolysaccharide (endotoxin) of gram negative organism has a core of lipid A and a complex polysaccharide coat. o Lipid A moiety of LPS bind to lipopolysaccharide binding protein and this complex then binds to CD-14 on the surface of monocytes, macrophages and neutrophils. o After that LPS is transferred to toll like receptor - o Signals from TLR-4 directly activate endothelium and leukocytes. ii) Gram positive bacteria may cause septic shock by : ? o Gram positive bacteria may cause septic shock by : ? i) Lipoteichoic acid of cell wall binds to toll like receptor-2 (TLR2) on the surface of monocyte/ macrophages and triggers the release of cytokines. ii) Superantigens are potent activators of T-lymphocytes. Superantigens bind directly to the lateral poion of TCR $ chain and MHC class II 13 chain and stimulate T-cells directly. Activated T-cells release IFN-y and IL-2 which stimulate macrophages to release primary cytotoxines. o All these result in release ofprimary cytokines. The impoant cytokines are TNF-a (most impoant cytokine in shock), IL-1 (2nd most impoant, IL-6). o After release of cytokines, the sequence of events is same for any type of septic shock : - a These cytokines activate endothelium and leukocytes which then release secondary mediators like NO, PAF, PG, LT, IL. (NO is responsible for vasodilation in septic shock). These secondary mediators cause vasodilatation, vascular leak and endothelial damage that results in shock. Release of excess primary mediators (cytokines) (TNF-a, IL-1, IL-6) Endothelial/leukocyte molecular activation Secondary mediators (NO, PAF, PG, LT, IL) Vasodilatation, capillary leak, endothelial damage Septic shock --> MODS --> Death So two mechanisms are impoant in septic shock :- i) Release of primary mediators of inflammation TNF? and IL-I. ii) Activation and damage to endothelium o Damage to endothelium leads to systemic inflammatory response which causes vasodilation and permeability leading to septic shock. o But the initial primary event is the release of primary mediators of inflammation cytokines as a result of interaction between bacterial cell wall components and host cell. The endothelium is subsequently activated and damaged by these mediators (cytokines). Therefore cvtokine release is the primary initiating factor in endotoxic shock. Infection (bacteria, fungi) Interaction of bacterial cell products with macrophages Release of primary mediation (cytokines) from macrophages Activation and damage to endothelium Release of secondary mediators o Vasodilation o Increased permeability o Decreased perfusion
Endothelial injury
Peripheral vasodilation
Increased vascular permeability
Cytokines action