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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL091842-05
Application #
8381591
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$295,983
Indirect Cost
$98,661
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Park, Jung-Eun; Li, Kun; Barlan, Arlene et al. (2016) Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism. Proc Natl Acad Sci U S A 113:12262-12267
Cooney, Ashley L; Abou Alaiwa, Mahmoud H; Shah, Viral S et al. (2016) Lentiviral-mediated phenotypic correction of cystic fibrosis pigs. JCI Insight 1:
Gibson-Corley, Katherine N; Meyerholz, David K; Engelhardt, John F (2016) Pancreatic pathophysiology in cystic fibrosis. J Pathol 238:311-20
Li, Xiaopeng; Tang, Xiao Xiao; Vargas Buonfiglio, Luis G et al. (2016) Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense. Am J Physiol Lung Cell Mol Physiol 310:L670-9
Shah, Viral S; Meyerholz, David K; Tang, Xiao Xiao et al. (2016) Airway acidification initiates host defense abnormalities in cystic fibrosis mice. Science 351:503-7
Tang, Xiao Xiao; Ostedgaard, Lynda S; Hoegger, Mark J et al. (2016) Acidic pH increases airway surface liquid viscosity in cystic fibrosis. J Clin Invest 126:879-91
Abou Alaiwa, Mahmoud H; Launspach, Janice L; Sheets, Kelsey A et al. (2016) Repurposing tromethamine as inhaled therapy to treat CF airway disease. JCI Insight 1:
Meyerholz, David K; Lambertz, Allyn M; McCray Jr, Paul B (2016) Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome. Am J Pathol 186:78-86
Hornick, Andrew L; Li, Ni; Oakland, Mayumi et al. (2016) Human, Pig, and Mouse Interferon-Induced Transmembrane Proteins Partially Restrict Pseudotyped Lentiviral Vectors. Hum Gene Ther 27:354-62
Meyerholz, David K (2016) Lessons learned from the cystic fibrosis pig. Theriogenology 86:427-32

Showing the most recent 10 out of 90 publications