Mukherjee, S., Giamberardino, C., Thomas, J., Evans, K., Goto, H., Ledford, J. G., Hsia, B., Pastva, A. M., & Wright, J. R. (2012). Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation. Journal of immunology (Baltimore, Md. : 1950), 188(3), 957-67.
Pulmonary surfactant lipoproteins lower the surface tension at the alveolar-airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A-mediated modulation of T cell activation depends upon the strength, duration, and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex vivo and in vivo in different mouse models and in vitro with human T cells shows a strong correlation between strength of signal (SoS) and functional effects of SP-A interactions. T cell proliferation is enhanced in the presence of SP-A at low SoS imparted by exogenous mitogens, specific Abs, APCs, or in homeostatic proliferation. Proliferation is inhibited at higher SoS imparted by different doses of the same T cell mitogens or indirect stimuli such as LPS. Importantly, reconstitution with exogenous SP-A into the lungs of SP-A(-/-) mice stimulated with a strong signal also resulted in suppression of T cell proliferation while elevating baseline proliferation in unstimulated T cells. These signal strength and SP-A-dependent effects are mediated by changes in intracellular Ca(2+) levels over time, involving extrinsic Ca(2+)-activated channels late during activation. These effects are intrinsic to the global T cell population and are manifested in vivo in naive as well as memory phenotype T cells. Thus, SP-A appears to integrate signal thresholds to control T cell proliferation.
Allen, I. C., Pace, A. J., Jania, L. A., Ledford, J. G., Latour, A. M., Snouwaert, J. N., Bernier, V., Stocco, R., Therien, A. G., & Koller, B. H. (2006). Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease. American journal of physiology. Lung cellular and molecular physiology, 291(5), L1005-17.
A genetic contribution to asthma susceptibility is well recognized, and linkage studies have identified a large number of genes associated with asthma pathogenesis. Recently, a locus encoding a seven-transmembrane protein was shown to be associated with asthma in founder populations. The expression of the protein GPRA (G protein-coupled receptor for asthma susceptibility) in human airway epithelia and smooth muscle, and its increased expression in a mouse model of asthma, suggested that a gain-of-function mutation in this gene increased the disease risk. However, we report here that the development of allergic lung disease in GPRA-deficient mice is unaltered. A possible explanation for this finding became apparent upon reexamination of the expression of this gene. In contrast to initial studies, our analyses failed to detect expression of GPRA in human lung tissue or in mice with allergic lung disease. We identify a single parameter that distinguishes GPRA-deficient and wild-type mice. Whereas the change in airway resistance in response to methacholine was identical in control and GPRA-deficient mice, the mutant animals showed an attenuated response to thromboxane, a cholinergic receptor-dependent bronchoconstricting agent. Together, our studies fail to support a direct contribution of GPRA to asthma pathogenesis. However, our data suggest that GPRA may contribute to the asthmatic phenotype by altering the activity of other pathways, such as neurally mediated mechanisms, that contribute to disease. This interpretation is supported by high levels of GPRA expression in the brain and its recent identification as the neuropeptide S receptor.
Addison, K. J., Morse, J., Robichaud, A., Daines, M. O., & Ledford, J. G. (2017). A Novel in vivo System to Test Bronchodilators. Journal of infectious pulmonary diseases, 3(1).
The incidence and severity of asthma continue to rise worldwide. β-agonists are the most commonly prescribed therapeutic for asthma management but have less efficacy for some subsets of asthmatic patients and there are concerns surrounding the side effects from their long-term persistent use. The demand to develop novel asthma therapeutics highlights the need for a standardized approach to effectively screen and test potential bronchoprotective compounds using relevant in vivo animal models. Here we describe a validated method of testing potential therapeutic compounds for their fast-acting efficacy during the midst of an induced bronchoconstriction in a house dust mite challenged animal model.
Guerra, S., Insel, M., Addison, K., Owen, C., Martinez, F., Kraft, M., & Ledford, J. (2017). Club cell secretory protein deficiency leads to altered lung function. Journal of Allergy and Clinical Immunology.
Ledford, J. G., Goto, H., Potts, E. N., Degan, S., Chu, H. W., Voelker, D. R., Sunday, M. E., Cianciolo, G. J., Foster, W. M., Kraft, M., & Wright, J. R. (2009). SP-A preserves airway homeostasis during Mycoplasma pneumoniae infection in mice. Journal of immunology (Baltimore, Md. : 1950), 182(12), 7818-27.
The lung is constantly challenged during normal breathing by a myriad of environmental irritants and infectious insults. Pulmonary host defense mechanisms maintain homeostasis between inhibition/clearance of pathogens and regulation of inflammatory responses that could injure the airway epithelium. One component of this defense mechanism, surfactant protein-A (SP-A), exerts multifunctional roles in mediating host responses to inflammatory and infectious agents. SP-A has a bacteriostatic effect on Mycoplasma pneumoniae (Mp), which occurs by binding surface disaturated phosphatidylglycerols. SP-A can also bind the Mp membrane protein, MPN372. In this study, we investigated the role of SP-A during acute phase pulmonary infection with Mp using mice deficient in SP-A. Biologic responses, inflammation, and cellular infiltration, were much greater in Mp infected SP-A(-/-) mice than wild-type mice. Likewise, physiologic responses (airway hyperresponsiveness and lung compliance) to Mp infection were more severely affected in SP-A(-/-) mice. Both Mp-induced biologic and physiologic changes were attenuated by pharmacologic inhibition of TNF-alpha. Our findings demonstrate that SP-A is vital to preserving lung homeostasis and host defense to this clinically relevant strain of Mp by curtailing inflammatory cell recruitment and limiting an overzealous TNF-alpha response.
