Chronic infection and intense inflammation are hallmarks of CF lung disease. Characteristics include colonization with bacteria and IL-8-driven, neutrophil predominant inflammation. However, a 'chicken and egg'conundrum regarding the chronology and causal relationship between inflammation and infection in the CF lung continues to plague the field. Existing mouse models of CF have helped advance our knowledge, but fail to develop the pulmonary phenotype characteristic of humans with CF. In this proposal a porcine model of CF (CFTR null) establishes the opportunity to study the onset of lung disease with approaches inconceivable in humans. By focusing on the prenatal and perinatal time periods, we may gain insights into underlying disease mechanisms without confounding variables. We will investigate key questions at the level of the intact animal and in specific cell-based models. We propose three aims.
Aim 1. Does the fetal porcine CF lung exhibit inflammation in the absence of infection? The time of onset of inflammation in the CF lung is not known. We hypothesize that loss of CFTR function predisposes the lung to a pro-inflammatory state in the absence of infectious or inflammatory stimuli. We will thoroughly query the late fetal CF and non-CF lung in vivo for evidence of inflammation.
Aim 2. Does the neonatal porcine CF lung develop inflammation spontaneously or in response to infection? We hypothesize that loss of CFTR function predisposes the newborn lung to spontaneous inflammation and causes enhanced or prolonged responses to infectious or inflammatory stimuli. In these studies the CF and non-CF piglets will be followed in clean housing, germfree isolators, or following specific microbial challenges for the development of spontaneous inflammation with or without infection as described in Aim 1. These approaches will allow a conclusive assessment of the spontaneous or inducible properties of the CF pig lung for developing inflammation.
Aim 3. How does loss of CFTR function alter specific innate immune functions in the CF pig? We hypothesize that loss of CFTR alters specific innate immune functions. These studies will address the following questions. We will perform experiments using primary cells from CF and non-CF animals to address the following question: 1) Does loss of CFTR function drive inflammatory responses in CFTR-/- epithelia in vitro?, 2) Do submucosal gland secretions exert an anti-inflammatory effect on the surface epithelium that is altered in CF?, and 3) Does the loss of CFTR function in macrophages and neutrophils contribute to inflammation in the CF lung? Our focus on the early onset of inflammation in the late fetal, early postnatal period allows the potential to mechanistically understand primary events negatively affecting the CF lung.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Iowa
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