Immune Response in Patients Who Develop Ventilator-Associated Pneumonia (VAP) in Intensive Care Unit (ICU) and the Role of Toll-Like Receptors(TLR2,TLR4,TLR9).

INTRODUCTION

Ventilator-associated pneumonia (VAP) typically refers to nosocomial pneumonia developing 48 hours later from endotracheal intubation and mechanical ventilation.ICU patients who receive mechanical ventilation have 4-fold higher risk of developing pneumonia with a rate of 3% per day after day 7 in the intensive care unit. Several risk factors have been reported to be associated with VAP, including the duration of mechanical ventilation, the presence of chronic pulmonary disease, sepsis, acute respiratory distress syndrome (ARDS), neurological disease and trauma. The immune system defends the host against infection. Protective immunity can be divided into innate and adaptive immunity. The innate immune response evolves as a first defence barrier in the host and mounts an immediate, but nonspecific, immune response to rapidly destroy or limit the invaders. The innate defense mechanisms are the external epithelia, the mucosal surfaces, the cells (NK cells, phagocytes) and the complement system.

Adaptive immunity is a second line defence that includes T (cellular) and B (humoral) cell mediated responses. This is specific, targets only pathogens and not self, and has memory to sustain a long-lasting immunity against reinfection. Although the innate immune system lacks the fine specificity of adaptive immunity it can distinguish self from non self. Innate immune recognition is mediated by a system of germline-encoded receptors named pattern recognition receptors (PRRs) that recognize conserved molecular patterns (pathogen-associated molecular patterns, PAMPs) that are associated with microbial pathogens. These receptors are coupled to signal transduction pathways that control expression of a variety of inducible immune-response genes.

TLRs control both innate and adaptive immune responses. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. TLR expression is observed in a variety of cells such as macrophages, neutrophils, dendritic cells, epithelial cells derived from gut, lung and derma, B-and T-lymphocytes.TLR4 was the first mammalian TLR identified and is involved in the recognition of lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria which can induce sepsis. TLR2 is the most powerful receptor and recognizes a wide variety of PAMPs from bacteria, yeast, fungi, parasites and viruses. TLR9 recognizes unmethylated CpG motifs present in bacterial DNA.

Sepsis syndrome is frequently complicated by the development of nosocomial infections, particularly Gram-negative pneumonia. Findings indicate that TLR9 serves as an important signal in the generation of protective innate responses to bacterial pathogens of the lung and that is required for effective innate immune responses against Gram-negative bacterial pathogens. Unmethylated CpG motifs are prevalent in bacterial but not vertebrate genomic DNA. The recognition of CpG motifs activates host defense mechanisms leading to innate and acquired immune responses. Cells that express TLR-9 are the plasmacytoid dendritic cells (PDCs) and the B cells and as a consequences produce Th1-like proinflammatory cytokines, interferons and chemokines. Activation of TLR-9 induces the production of a) cytokines (IL-12, IL-1, IL-6, IL-8), interferon (IFN)-γ and tumor necrosis factor (TNF-)α which are Th1 proinflammatory cytokines and b) IL-10 and IL-4 which are Th2 proinflammatory cytokines that induce immunosuppression.