| Background:The generation of inflammatory response is a critical mechanism through which mammalian species respond to and protect themselves from infections as well as that from noninfectious insults. In terms of the lung, both nonspecific and antigen-specific mechanisms may lead to inflammatory response. While this response is usually protective and beneficial, inflammation also has the potential to cause tissue injury within the lungs. The lungs exposed to risk factors such as immaturity, meconium aspiration, barotrauma, and infection frequently develop acute lung injury (ALI). These injuries, occurring in developmentally and structurally immature lungs are thought to contribute to the pathogenesis of neonatal respiratory stress syndrome (RDS) and chronic lung disease (CLD) in infancy. As a major effector of the innate immune system of the body, alveolar macrophages (AM) interact with other cells in airways and alveoli immediately after birth, resulting in generation of intracellular signaling cascade, leading to various effects or functions that make up the initial immune response in the lungs. Interaction of lipopolysaccharide (LPS) or bacterial infection with AM causes a sequential activation of multiple signaling pathways and transcription factors, resulting in gene transcription. This process orchestrates production of both pro- and anti-inflammatory mediators. Two well-defined transcription factors influenced by inflammation are nuclear factor (NF)-B and activator protein (AP)-1, which play significant roles in regulation of the production of many inflammatory mediators. NF-B is an ubiquitous transcription factor complex that directs high-level transcription of many cytokines, adhesion molecules, and proinflaminatory cytokine genes. NF- B activation is linked to production of TNF-a, IL-1, IL-6, IL-8, IL-10, to name just a few of the genes with active NF- B sites. AP-1 transcription factors has attracted much attention for numerous investigations, as theyplay critical roles in regulating target genes involved in adaptive responses to inflammation. In newborns with immature lung, this mechanism is not fully understood yet. Proinflammatory cytokines such as tumor necrosis factor- a (TNF), interleukin (IL)-l 15, 1L-6 and IL-8 have been recovered from airway aspirated (AA) of premature infants with RDS and may be responsible for the recruitment of inflammatory cells into the pulmonary milieu. In addition, increased messager ribonucleic acid (RNA) expressions of various cytokines have been observed in inflammatory cells present in AA from infants with CLD. However, the onset of this process and intrauterine characteristics of inflammatory reactions remain unclear. Further understanding of the mechanisms and signal transduction pathways of pulmonary inflammation in RDS and ALI may lead to new strategy and technology for prevention and treatment. Nitric oxide (NO), glucocorticoids (GC), surfactant (Surf) are important endogenous regulatory molecules in lung inflammation and infection leading to ALI There are limited evidence regarding the role of AM of the lungs subjected to mechanical ventilation with respect to exogenous NO, Surf and GC in the activating process of NF-B and AP-1. We hypothesized that NO, GC and Surf may regulate NF- B and AP-1 activation in AM from ventilated animals with lung inflammation induced by sepsis,meconium and hyperoxia, and altered expression of NF- B in AM from newborn infants with respiratory distress syndrome (RDS). We also investigated proinflammatory cytokine expression in fetal and neonatal lung tissue of chorioamnionitis.Objectives:1. To investigate the activity of NF-B in lung tissue of animal model of ALI by bacterial infection and meconium aspiration and subjected to mechanical ventilation, and assess different effects of NO and surfactant treatments.2. To establish a method to obtain in vivo "silent" or inflammation activated AM as characterized by their response to in vitro stimulations leading to up- or down-regulation of expression of NF-icB and AP...
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