Publications

Pulmonary alveolar type I cells (TI cell) are very large (approximately 5400 microm(2) in surface area) squamous cells that cover more than 98% of the internal surface area of rodent lungs. In the past, TI cells were believed to serve only passive barrier functions, with no active functional properties in the lung. The fairly recent development of methods to isolate TI cells has permitted investigation of functions of this cell type for the first time. Resolvable by electron microscopy, TI cells contain microvilli and organelles typically associated with metabolic functions, such as mitochondria, abundant smooth and rough endoplasmic reticulum and Golgi apparatus. TI cells contain the molecular machinery necessary for ion transport and take up Na(+), K(+), and Cl(-), from which one can infer that it is likely that they play a role in ion and fluid transport in vivo. Because the abundance/microm(2) of highly selective Na(+) channels (HSC channels, consisting of all three ENaC subunits) is the same in TI and TII cells and because TI cells cover the majority of the lung internal surface, TI cells may play the major role in bulk transport of Na(+). In vitro, TI cells can proliferate and exhibit phenotypic plasticity, raising the question of whether this cell type may play a role in development and lung repair after injury. From gene expression analysis of TI cells, one can infer a variety of other possible functions for TI cells. The development of techniques to administer transgenes specifically to TI cells will permit direct study of this cell type in vivo.

Whether genetic factors account for differences in early kidney disease among blacks in a young healthy population is not well known. We evaluated the association of self-reported race and genetic African ancestry with elevated creatinine (> or =1.3 mg/dl for men, > or =1.1 mg/dl for women) among 3,113 black and white participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 38-50 years. We estimated individual African ancestry using 42 ancestry informative markers. Blacks were more likely to have elevated creatinine than whites, and this effect was more pronounced in men: adjusted odds ratio (AOR) for black versus white men = 7.03, 4.15-11.91; AOR for women = 2.40, 1.15-5.02. Higher African ancestry was independently associated with elevated creatinine among black men (AOR = 1.53,1.08-2.16 per SD increase in African ancestry), but not women. A graded increase in odds of elevated creatinine by African Ancestry was observed among black men compared with white men: AOR = 4.27 (2.26-10.06) for black men with 40-70% African ancestry; AOR = 8.09 (4.19-15.61) for black men with 70-80% African ancestry; AOR = 9.05 (4.81-17.02) for black men with >80% African ancestry. Genetic factors common to African ancestry may be associated with increased risk of early kidney dysfunction in a young, healthy population, particularly among black men.

Immunity to Mycobacterium tuberculosis in humans and in mice requires interferon gamma (IFN-gamma). Whereas IFN-gamma has been studied extensively for its effects on macrophages in tuberculosis, we determined that protective immunity to tuberculosis also requires IFN-gamma-responsive nonhematopoietic cells. Bone marrow chimeric mice with IFN-gamma-unresponsive lung epithelial and endothelial cells exhibited earlier mortality and higher bacterial burdens than control mice, underexpressed indoleamine-2,3-dioxygenase (Ido1) in lung endothelium and epithelium, and overexpressed interleukin-17 (IL-17) with massive neutrophilic inflammation in the lungs. We also found that the products of IDO catabolism of tryptophan selectively inhibit IL-17 production by Th17 cells, by inhibiting the action of IL-23. These results reveal a previously unsuspected role for IFN-gamma responsiveness in nonhematopoietic cells in regulation of immunity to M. tuberculosis and illustrate the role of IDO in the inhibition of Th17 cell responses.