Endotoxin Effects on Cardiopulmonary Function in Healthy Volunteers

Endotoxin is a unique molecule because it represents an important probe for investigating the humoral and cellular basis of septic shock. Endotoxin administration to humans provides an opportunity to evaluate the earliest responses that are activated after exposure to an important bacterial component. Many alterations in organ function and circulating mediators can be evaluated in this model. These changes are qualitatively similar to changes that occur during sepsis and septic shock. The applications of new technologies to this model are useful adjuncts to define mechanisms of acute inflammatory responses. Defining these pathways and their interactions may allow a better understanding of the factors that can be controlled or altered during critical illness. In the current study, we are planning to extend previous observations on heart and lung function after endotoxin administration in four separate studies. Bronchoalveolar lavage and bronchial brushings in normal subjects. Bronchoalveolar lavage and bronchial brushings will be performed in normal subjects to obtain alveolar and epithelial pulmonary cells for use in vitro assays of respiratory cell function. Inflammatory effects of systemic endotoxin administration. In order to evaluate late inflammatory responses to IV endotoxin, blood will be obtained acutely and at 1, 2, 3, 7, and 14 days post endotoxin challenge. Pulmonary effects of instilled endotoxin. Using bronchoscopy, the effects of direct instillation of endotoxin into a lobe of the lung is being used to assess local pulmonary inflammatory responses that result in neutrophil influx into the lung. Effects of inhaled nitric oxide on pulmonary inflammatory responses following endotoxin administration. In order to systematically study the effects of inhaled nitric oxide on local lung inflammation, healthy subjects will undergo local endotoxin instillation, breath NO through a mask for 6h, and then a repeat bronchoscopy will be done at 6h to assess the ability of NO to suppress local inflammation in the lung.