Activation of innate immunity in the lungs can lead to a self-limited inflammatory response or progress to severe lung injury. We investigated whether specific parameters of NF-κB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single i.p. injection of Escherichia coli LPS, transient NF-κB activation was identified in a variety of lung cell types, and neutrophilic inflammation resolved without substantial tissue injury. However, administration of LPS over 24 h by osmotic pump (LPS pump) implanted into the peritoneum resulted in sustained, widespread NF-κB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-κB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IκB kinase inhibitor (BMS-345541) to down-regulate NF-κB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-κB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-κB activation correlates with severity of lung injury, and interdiction in the NF-κB pathway is beneficial even after the onset of lung inflammation.

Malignancy involving the pleura is the third leading cause of pleural effusions, with an annual incidence of Ͼ 150,000 cases in the United States (1, 2). Adenocarcinomas account for ‫ف‬ 70% of all malignant pleural effusions (MPEs), with lung adenocarcinomas being the most frequent underlying malignancy (3). The appearance of a MPE is an ominous prognostic sign for patients with cancer, because the presence of the MPE indicates that the tumor is incurable by surgery and life expectancy is short (1). In addition, the presence of the pleural effusion can cause dyspnea that severely compromises the quality of the patient's life (4, 5). Pleurodesis, the iatrogenic induction of pleural fibrosis to obliterate the pleural cavity, is commonly used to prevent symptomatic re-accumulation of pleural effusions; however, this therapy is often ineffective and is associated with significant It is generally believed that disruption of the endothelialmesothelial barrier, increased capillary permeability, tumorinduced angiogenesis, and lymphatic obstruction are responsible for the exudation of increased amounts of fluid into the pleural cavity (1, 7). However, the specific mechanisms underlying pleural fluid accumulation are poorly defined because studies of MPE pathogenesis are limited by a lack of animal models that reproduce the pathobiology of human MPE. Although mouse models that require immunocompromised mice for propagation of human cancer cells mice have provided insights into the biological behavior of tumor cells in the pleural cavity (7-9), these models are not ideal because the host is immunocompromised, and, therefore, the host immune response is attenuated or missing. The immune response against tumor may be an important component in the development of MPE because host inflammatory cells may contribute to or regulate the production of mediators that affect pathogenesis (10).Nuclear factor (NF)-B is a ubiquitous family of transcription regulatory proteins that affects a variety of cellular functions and influences tumor biology and host-tumor interactions. NF-B is activated by a number of tumor-promoting agents and is involved in the production of proteins that enhance cell survival and proliferation (11). High basal NF-B activation is present in lung adenocarcinoma cells and human lung cancer, and inhibition of NF-B sensitizes tumor cells to apoptosis and the effects of chemotherapeutic agents (11)(12)(13)(14)(15).Lewis lung cancer (LLC) cells are derived from a spontaneously arising lung adenocarcinoma in C57B/6 mice. These cells are characterized by short doubling times in vitro and in vivo and aggressive biological behavior. They can be propagated in wild-type C57B/6 mice, giving rise to lung adenocarcinomas (16)(17)(18). In these studies, we have developed and characterized a new murine model of MPE after instillation of lung adenocarcinoma cells in the pleural space of immunocompetent mice. We used this model to investigate whether the NF-B pathway in tumor cells is linked to MPE formation and progression of pl...

We investigated the impact of inflammatory signaling in airway epithelial cells on host defense against Pseudomonas aeruginosa, a major cause of nosocomial pneumonia. In mice, airway instillation of P. aeruginosa resulted in NF-κB activation in the lungs that was primarily localized to the bronchial epithelium at 4 h, but was present in a variety of cell types by 24 h. We modulated NF-κB activity in airway epithelium by intratracheal delivery of adenoviral vectors expressing RelA (AdRelA) or a dominant inhibitor of NF-κB before P. aeruginosa infection. Bacterial clearance was enhanced by up-regulation of NF-κB activity following AdRelA administration and was impaired by treatment with a dominant inhibitor of NF-κB. The TNF-α concentration in lung lavage was increased by AdRelA treatment and beneficial effects of NF-κB up-regulation were abrogated in TNF-α-deficient mice. In contrast, NF-κB inhibition reduced MIP-2 expression and neutrophil influx following P. aeruginosa infection. Therefore, inflammatory signaling through the NF-κB pathway in airway epithelial cells critically regulates the innate immune response to P. aeruginosa.