There is growing evidence that surfactant-associated proteins A (SP-A) and D (SP-D) mediate interactions between the host and inhaled microorganisms. These collagenous lectins (collectins) show specific interactions with conserved structural components and virulence factors expressed on the surfaces of a wide variety of microorganisms. The ligands include gram- negative lipopolysaccharides (LPS), the capsular polysaccharides (CPS) of specific encapsulated strains of Klebsiella pneumoniae (Kp), and the hemagglutinin of influenza A virus (IAV). Lung collectins also modulate the function of leukocytes, both through direct interactions with specific receptors and by altering the presentation of microorganisms as a consequence of microbial aggregation. We hypothesize that SP-A and SP-D are functionally complementary by virtue of their capacity to interact with different structures variably displayed on the surface of gram- negative bacteria, and that their combined interactions influence the responses of phagocytic cells. We further hypothesize that SP-D directly modulates the phenotype of macrophages and that the lung collectins indirectly modulate the response of these cells to LPS. Because specific strains of Kp have been shown to interact with both SP-A and SP-D, we propose to examine the interactions of human SP-D and SP-A with strains of Kp and Kp LPS, to characterize the SP-D mediated opsonization of Kp, to study the effects of environmental modulation of LPS and CPS expression on the interactions of the collectins with these organisms, and to examine the effects of soluble Kp CPS on the host defense activities of SP-A. We also propose to examine the effects of SP-D on the production of selected cytokines (e.g., TNF-alpha) and metalloproteinases by monocyte/macrophages to evaluate the contribution of GP-340 (a putative SP-D receptor) to the regulation of altered cytokine and metalloproteinase production and bacterial opsonization, and to determine whether lung collectins can modulate the effects of LPS on macrophage cytokine production by altering the interactions of LPS with LPS binding protein (LBP) or LPS receptor (CD14). Finally, we propose to further define the structural features of SP-D required for the aggregation dependent modulation of phagocyte function. We anticipate that the proposed studies will yield important new information relation to the biologic activities of lung collectins and the response of the lung to gram-negative organisms, gram-negative LPS, and respiratory viruses.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Barnes-Jewish Hospital
Saint Louis
United States
Zip Code
Byers, Derek E; Wu, Kangyun; Dang-Vu, Geoffrey et al. (2018) Triggering Receptor Expressed on Myeloid Cells-2 Expression Tracks With M2-Like Macrophage Activity and Disease Severity in COPD. Chest 153:77-86
Wu, Kangyun; Byers, Derek E; Jin, Xiaohua et al. (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med 212:681-97
Gharib, Sina A; Edelman, Jeffery D; Ge, Lingyin et al. (2015) Acute cellular rejection elicits distinct microRNA signatures in airway epithelium of lung transplant patients. Transplant Direct 1:
Holtzman, Michael J; Byers, Derek E; Brett, Jennifer-Alexander et al. (2014) Linking acute infection to chronic lung disease. The role of IL-33-expressing epithelial progenitor cells. Ann Am Thorac Soc 11 Suppl 5:S287-91
Gu, Xiaoling; Karp, Philip H; Brody, Steven L et al. (2014) Chemosensory functions for pulmonary neuroendocrine cells. Am J Respir Cell Mol Biol 50:637-46
Pan, Jie-Hong; Adair-Kirk, Tracy L; Patel, Anand C et al. (2014) Myb permits multilineage airway epithelial cell differentiation. Stem Cells 32:3245-56
Rohani, Maryam G; Pilcher, Brian K; Chen, Peter et al. (2014) Cdc42 inhibits ERK-mediated collagenase-1 (MMP-1) expression in collagen-activated human keratinocytes. J Invest Dermatol 134:1230-1237
Holtzman, Michael J; Byers, Derek E; Alexander-Brett, Jennifer et al. (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14:686-98
Byers, Derek E; Alexander-Brett, Jennifer; Patel, Anand C et al. (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest 123:3967-82
Chen, Peter; Edelman, Jeffrey D; Gharib, Sina A (2013) Comparative evaluation of miRNA expression between in vitro and in vivo airway epithelium demonstrates widespread differences. Am J Pathol 183:1405-1410

Showing the most recent 10 out of 333 publications