Wagener 2015 sm crBrant Wagener, M.D., Ph.D.The primary, global question that our lab seeks to answer is “how does acute critical illness become chronic critical illness?” When patients become severely critically ill in the Intensive Care Unit (ICU), there is ~25% mortality. Of the 75% that survive their stay in the ICU, ~50% will die in the next 1-2 years. Additionally, there is post-ICU cognitive dysfunction that occurs as a result of critical illness, regardless of mortality during the next two years. This mortality and morbidity is costly to patients in terms of their ability to take care of their families and to society in terms of health-care costs, days of work missed and other burdens. We seek to understand why patients that survive acute critical illness have ongoing morbidity and mortality that severely impairs their life and society at-large.

We currently work on two projects that are subsets of the aforementioned larger goals: 

The Role of Sex Dimorphism in post-TBI Bacterial Pneumonia

Traumatic brain injury (TBI) is the leading cause of injury-related death in patients under the age of 46 years. Survivors of the initial brain injury face numerous extracranial complications that are a major determinant of long-term outcome and impede their most productive years of life. Post-TBI pulmonary infection rate is as high as 50-60% and results in an infection-related mortality rate of ~30%. After severe TBI, the parasympathetic nervous system is activated to attenuate the systemic inflammatory response and may prevent some post-TBI, non-brain end-organ injury. However, parasympathetic nervous system activation may be maladaptive and results in dysregulation of alveolar macrophage and neutrophil immune function. Thus, parasympathetic-induced α7nAChR activation leads to a maladaptive lung innate immune response leading to greater severity and mortality in post-TBI bacterial pneumonia.

Interestingly, female patients have a lower incidence of post-TBI lung infection compared to males with equivalent TBI severity. Finally, estrogen restores NF-κβ activation, TNF-α release and phagocytic function. Hence, sex differences play a crucial role in post-TBI α7nAChR activation and how estrogen alleviates the α7nAChR-dependent maladaptive response and improves survival from pneumonia after TBI is of great clinical importance.

We use a reverse translational approach and hypothesize that parasympathetic-induced, α7nAChR-mediated dysregulation of alveolar macrophage and neutrophil immune function leads to decreased lung bacterial clearance and survival in post-TBI P. aeruginosa-induced lung infection and is alleviated by estrogen.

We address these questions with three Specific Aims: 1) α7nAChR activation leads to a dysregulated, maladaptive innate immune response leading to decreased lung bacterial clearance and survival after post-TBI P. aeruginosa infection; 2) Sex differences in parasympathetic-induced α7nAChR maladaptive signaling leading to lung innate immune dysfunction are alleviated by estrogen; 3) Examine the sex differences in response to α7nAChR activation of innate immune cells after TBI in humans. 

Role of amyloid beta (Aβ) in bacterial pneumonia-mediated lung injury

A recently published NHBLI working group report emphasized the importance of two erroneous paradigms that have limited our understanding of the role of bacterial pneumonia on health and have compromised the research agenda on pneumonia. The first erroneous paradigm is that pneumonia is a localized disease. In fact, pneumonia causes end-organ injury by mechanisms that are poorly understood. The second erroneous paradigm is that pneumonia is an acute disease. Clinical manifestations present during the acute episode persist long after resolution of the primary infection, such as delirium, skeletal muscle weakness or acute kidney injury leading to chronic kidney disease. Pneumonia also accelerates subclinical and overt chronic diseases and is thus a leading cause of patient readmission to the hospital after home or institutional discharge. Thus, how biological changes during pneumonia induce long-term morbidity – such as the development of persistent inflammatory, immunosuppressed, catabolic syndrome that leads to multiorgan failure– is an important question that is only beginning to be addressed.

Pseudomonas (P.) aeruginosa is a common cause of nosocomial pneumonia in intensive care units. It is a Gram-negative bacterium that can inject multiple exoenzymes, most notably ExoY and ExoU, into cells via the Type III Secretion System. P. aeruginosa is known to cause derangements in paracellular permeability and net alveolar fluid transport in alveolar epithelial cells. Our collaborators have recently demonstrated that P. aeruginosa elicits oligomeric tau and amyloids from pulmonary endothelial cells, and that oligomeric tau and amyloids cause cytotoxicity and impair cognitive function. As alveolar epithelial cells are among the first cells to encounter invading bacteria, a better understanding of the mechanisms by which P. aeruginosa elicits amyloids from epithelial cells and the inhibition of normal epithelial function that ensues is paramount.

We seek to test the hypothesis that P. aeruginosa-induced release of epithelial Aβ causes an increase in alveolar epithelial permeability and inhibition of transepithelial ion transport.

We will address these hypotheses by: determine whether P. aeruginosa infection-induced epithelial Aβ 1) increases alveolar epithelial paracellular permeability; 2) inhibits ion and fluid transport via desensitization and downregulation of β2-adrenergic receptor signaling; 3) determine whether administration of antibiotics can stop release of Aβ; 4) determine whether Aβ can propagate to other cell types; 5) determine whether there are any adjunct therapies that can inhibit the release/propagation of Aβ.