Regional Center for Newborn Intensive Care (RCNIC)

Paul S. Kingma, MD, PhD

Appointment

Assistant Professor of Pediatrics, University of Cincinnati College of Medicine

Email

paul.kingma@cchmc.org

Phone

513-636-2995

Fax

513-636-7868

Bio

Each day the human lung exchanges approximately 15,000 liters of air that contains a multitude of microorganisms and fine particles. Despite the absence of a rigid protective physical barrier at the air-tissue interface, the lung is infrequently subjected to infection or injury by toxicants. Pulmonary homeostasis is maintained in large part by multilayered immune system that simultaneously defends ~150 m2 of lung surface area from microbial invasion and maintains the integrity of the alveoli. Research in my lab focuses on two main components of the pulmonary immune system, surfactant protein D (SP-D) and neutrophil mediated bacterial killing.

SP-D is a critical component of the pulmonary innate immune system and a member of the collectin family of proteins. In the lung, SP-D binds bacterial, viral, and fungal pathogens and facilitates the clearance of these organisms. Mice with targeted deletion of the SP-D gene have defects in microbial clearance from the lung. In addition, they have an exaggerated inflammatory response during pulmonary infection suggesting that SP-D also has critical roles in regulating pulmonary host defense cells and limiting inflammatory tissue injury. In addition to the lung, SP-D is also detected in lower concentrations in blood and many other non-pulmonary tissues; however, the source and functions of extrapulmonary SP-D are unknown. Our results suggest that SP-D has a clinically relevant role in host defense beyond the pulmonary system and that SP-D may provide a link between circulating innate defense proteins and the vascular endothelium. Therefore, my laboratory is currently testing the general hypothesis that SP-D clears infectious pathogens and decreases inflammatory tissue injury in extrapulmonary systems and that SP-D may be used as a therapeutic agent designed to limit tissue injury and improve survival in systemic sepsis.

Cystic fibrosis (CF) is a complex inherited lethal disease that is caused by mutations in CFTR. The majority of the clinical pathology associated with CF arises from chronic pulmonary infection and inflammation. A hallmark of inflammation in CF is a persistent neutrophilic airway infiltration that develops early in life and is thought to be one of the main causes of airway destruction observed in CF. Whether the neutrophilic infiltration in CF is due to an abnormality in the CF airway, constant pulmonary infection, or a primary defect in the CF neutrophil is unclear. Moreover, the paradox of why this large influx of neutrophils fails to eradicate bacteria from the CF lung has yet to be explained. In alveolar macrophages, CFTR is required to acidify phagosomes and subsequently kill engulfed bacteria. Recently, CFTR was also detected in neutrophil phagolysosomes, suggesting CFTR may have a similar role in neutrophil mediated bacterial killing. Since macrophages and neutrophils utilize many of the same mechanisms in phagocytic killing of bacteria, we are testing the hypothesis that neutrophils from CF patients are intrinsically abnormal and that CFTR is required for intracellular killing of bacteria by neutrophils. The logical extension of our general hypothesis is that if neutrophils are unable to kill ingested bacteria, this defect would set in motion a self perpetuating cycle of persistent infection, increasing inflammation and lung injury. If our hypothesis is correct, these experiments will help explain the persistent infections and chronic inflammation that afflict CF lungs.

Credentials

Fellowship: Neonatology, Cincinnati Children's Hospital Medical Center, 2005

Residency: Pediatrics, Cincinnati Children's Hospital Medical Center, 2003

PhD: Vanderbilt University, TN, 2000

MD: Vanderbilt University, TN, 2000

BS: Calvin College, MI, 1992

Position History

Assistant Professor of Pediatrics, Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 2005-present

Awards and Honors

Reginald Tsang Award, Cincinnati Children’s Hospital Medical Center, 2004
Neonatology Award, Cincinnati Children's Hospital Medical Center, 2003
John G. Coniglio Prize in Biochemistry, Vanderbilt University, 2000
ASBMB Young Scientist Travel Fellowship, 1997
Honors Convocation, Calvin College, 1988-1992
Faculty Honors Scholarship, Calvin College, 1988-1992

Research

Innate Immune Systems
Surfactant Protein D
Neutrophil function in Cystic Fibrosis

Research Grants and Contracts

Surfactant Protein D in Systemic Infection and Inflammation. Translational Research Initiative, Cincinnati Children's Hospital Medical Center 07/01/06 - 06/30/07, PI

NIH/NICHHD K12: Pediatric Center for Gene Expression and Development. 07/01/07 – 06/30/08

NIH/NHLBI K08: Surfactant protein D in Systemic Infection and Inflammation. 07/01/08 - 06/30/13, PI

Neutrophil Function in Cystic Fibrosis. CFF 09/01/08 - 08/31/10

Publications, Most Recent

Mierke SK, Moreland R, Scheule R, Brondyke W, Kingma PS. Intravenous Surfactant Protein D Inhibits Lipopolysaccharide-Induced Systemic Inflammation by Direct Interactions with Vascular Endothelial Cells. Am J Respir Crit Care Med 2009 (In preparation).

Vuletin JF, Cnota J, Kline-Fath B, Lim F, Haberman B, Kingma PS, Frischer J, Crombleholme T. Prenatal pulmonary hypertension index (PPHI): Novel prenatal predictor of severe postnatal pulmonary artery hypertension in antenataly diagnosed congenital diaphragmatic hernia. J Ped Surg 2009 (Submitted).

White M, Kingma PS, Tecle T, Kacak N, Linders B, Heuser J, Crouch E, Hartshorn K. Multimerization of surfactant protein D, but not its collagen domain, is required for antiviral or opsonic activities related to influenza A virus. J Immunol 2008;181:7936.

Kingma PS, Whitsett JA.In defense of the lung: surfactant protein A and surfactant protein D. Curr Opin Pharmacol 2006;6:277-83.

Kingma PS, Zhang L, Ikegami M, Hartshorn K, McCormick F, Whitsett JA. Correction of Pulmonary Abnomalities in Sftpd-/- Mice Requires the Collagenous Domain of Surfactant Protein D. J Biol Chem 2006;281:24496-505.

Presentations, Most Recent

Kingma, P.S., Mierke, S.K., Haaning, K. Intravenous Surfactant Protein D Inhibits Lipopolysaccharide-Induced Systemic Inflammation by Direct Interactions with Vascular Endothelial Cells, FASEB Summer Research Conference Lung Epithelium in Development and Disease, August, 2008.

Kingma, P.S. Rules of the rule out: Diagnosing neonatal infection, OIKAAN Meeting, Mason, OH, May, 2008.

Kingma, P.S., Mierke, S.K. Intravenous surfactant protein D inhibits lipopolysaccharide-induced systemic inflammation by interactions with vascular endothelial cells, Ohio Perinatal Club, Columbus, OH, April, 2007.

Kingma, P.S. Intravenous surfactant protein D inhibits lipopolysaccharide-induced systemic inflammation, Ohio Perinatal Club, Columbus, OH, April, 2006.