Cell Signaling Research

Vermont Lung Center

Janssen-Heininger Bio

The Janssen-Heininger laboratory is interested in the role of lung epithelial cells in asthma and related lung disorders. Asthma is a disease that affects millions of Americans and is the leading cause of children missing school. We study the molecular signaling events that dictate survival and death of the lung epithelium, since protracted turnover of lung epithelium is a critical factor in regulating lung remodeling. The oxidant, nitrogen dioxide is formed in lungs from asthmatics and believed to contribute to inflammation and airway injury. The laboratory addresses the mechanisms by which nitrogen dioxide evokes damages lung epithelium and aggravates of inflammation. Areas of investigation involve the transcription factor, nuclear factor kappa B, the c-Jun-N-terminal kinase signaling pathway, and the death receptor, Fas. We have generated a transgenic mouse model and will design a targeted knock out animal to address the importance of these proteins in the disease pathology.

The separate lines of research are described in further detail below:

Molecular mechanisms of NO2-induced cell death:

The first line of research focuses on nitrogen dioxide, or NO2. NO2 is an important airpollutant that aggravates asthma in children upon inhalation. More important is the fact that NO2 can also be formed within the lung as a result of complicated chemistry that involve products of nitric oxide. At this time, the relevance of endogenously formed NO2 in damage associated with inflammation as well as pulmonary remodeling is completely unknown. We therefore are elucidating mechanisms by which NO2 damages cells. We know now that migrating or dividing cells are exquisitely sensitive to NO2 whereas quiescent cells are resistant. We know that the NO2 gas has to react directly with the cells to cause cell death and that mitogen activated protein kinases and death receptors are involved. We are currently investigating patterns of injury in a mouse model. This provides avenues for the use of transgenic and knock-out models, enabling us to causally link signaling pathways to lung injury.

Allergic airway disease in the mouse:

The second line of investigation focuses on a model of allergic airway disease in mice. This model which utilizes immunization and challenge of the lung with an antigen evokes a response in the mouse that resembles asthma in humans. We would like to understand the importance of the bronchiolar epithelium, the first cell to contact inhaled matter, in this model of lung disease. We believe that the activation of NF-kB in this cell type is crucial to the disease. Using a transgenic mouse model, we are testing this hypothesis. We are also elucidating where in the lung NF-kB is activated and what NF-kB regulated genes play a role. Coupling lasermicrodissection with microarray analysis provide exciting avenues to address these crucial questions.

Nitrogen dioxide and the aggravation of inflammation:

The third line of investigation seeks to determine how products of inflammation, such as reactive oxygen and nitrogen species, or cationic proteins affect signaling events that are important ultimately in remodeling of the lung such as narrowing of the airways, that makes breathing difficult in patients with asthma. This is a challenging project since these factors interact with cells in very unique ways that do not involve classic surface receptors directly. For example, we are determining how oxidants such as NO2 prolong inflammatory signaling and whether this involves NF-kB. Cationic proteins are unique molecules are required for asthma in the mouse. The interaction with epithelium appears to be crucial but the signaling events that are activated are obscure.

Inflammation and muscle wasting:

The fourth line of investigation currently ongoing in the laboratory is aimed at elucidating mechanisms that are associated with muscle wasting. We have determined that tumor necrosis factor prevents myogenic differentiation of myogenic precursor cells and that NF-kB and oxidative stress are causally linked to this event. We are currently performing experiments to determine whether this also occurs in an mouse model. Experiments are ongoing to determine the altered regulation of myogenic transcription factors during inflammation. This project is performed in collaboration with the Department of Pulmonology at Maastricht University in Maastricht, the Netherlands.