Research

Boggaram, Vijay, Ph.D.

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Contact: vijay.boggaram@uthct.edu

Education:
M.S., Biochemistry, 1975, University of Mysore, India
Ph.D., Biochemistry, 1982, University of Stockholm, Sweden

Research Interest:
Regulation of gene expression in the lung.

Current Projects:
Regulation of surfactant protein and interleukin 8 (IL-8) gene expression in lung epithelial cells.

Lay Summary:
Surfactant proteins are important constituents of surfactant, a lipid-protein complex, which maintains lung stability and plays important roles in the control of innate immunity in the lung. Surfactant levels are significantly reduced in premature infants and in individuals with inflammatory lung diseases such as acute respiratory distress syndrome (ARDS), bacterial and viral infections and others. Decreased levels of surfactant are thought to contribute to lung injury that occurs in these diseases. In particular reduction in the levels of surfactant protein B (SP-B), a hydrophobic protein of surfactant, is believed to be an underlying factor responsible for lung injury as SP-B is absolutely required for surfactant function. Interleukin 8 (IL-8) is a chemokine that is a potent chemoattractant and an activator for neutrophils, T cells and other immune cells. IL-8 levels are directly correlated with neutrophil content and severity of lung injury in lung inflammatory diseases. A number of agents including tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and others have been implicated as causative agents in the aberrant expression of surfactant protein and IL-8 genes in lung inflammatory diseases.

Our research is focused on the understanding of molecular mechanisms that mediate altered expression of surfactant protein and IL-8 genes in lung cells by TNF-alpha, nitric oxide and others implicated in tissue injury in inflammatory lung diseases.

Research Overview:
Our initial studies focused on the understanding of molecular regulation of surfactant proteins (SP) -B and C by glucocorticoids and cyclic AMP in fetal lung tissues. Glucocorticoids and cAMP have profound effects on fetal lung maturation and surfactant synthesis. We cloned rabbit SP-B and SP-C cDNAs, and using rabbit fetal lung tissues in explant culture showed that glucocorticoids and cAMP have significant inductive effects on SP-B and SP-C mRNAs. The inductive effects of glucocorticoids were largely exerted at the posttranscriptional level via stabilization of SP-B and SP-C mRNAs. On the other hand the inductive effects of cAMP were due to increases in gene transcription. Our studies also showed that posttranscriptional mechanisms contribute to the developmental induction of SP-B and SP-C mRNAs.

SP-B is expressed in a highly cell/tissue restricted manner in the alveolar type II and Clara bronchiolar epithelial cells of the lung. Using transient transfection assays and transgenic mice, we showed that as little as -236/+39 bp of rabbit SP-B 5’ flanking DNA is necessary and sufficient for cell-specific and developmental regulation of SP-B expression. The minimal SP-B promoter region contained binding sites for ubiquitous (Sp1/Sp3, ATF/CREB) and cell-restricted (TTF-1 and HNF-3) transcription factors which interacted in a combinatorial manner to maintain SP-B promoter activity. The promoter activity was sensitive to alterations in the relative positions and orientations of binding sites indicating that stereospecific interactions between transcription factors are necessary for promoter activation.

Inflammatory diseases of the lung such as acute respiratory distress syndrome (ARDS) are characterized by elevated levels of TNF-alpha and nitric oxide. Increased levels of TNF-alpha and nitric oxide are associated with abnormal surfactant function indicating that surfactant components may be negatively regulated. Our studies showed that TNF-alpha and nitric oxide inhibit SP-B mRNA levels in H441 (Clara) and MLE-12 (type II) lung epithelial cells by inhibiting gene transcription. The inhibitory effects of TNF-alpha in H441 cells were mediated via inhibition of DNA binding activities of TTF-1 and HNF-3 transcription factors.
Inflammatory diseases of the lung are characterized by increased infiltration of neutrophils into air spaces. Interleukin 8 (IL-8) plays a major role as a chemoattractant agent for neutrophils. As the lung epithelium is capable of producing elevated levels of NO during inflammation, we proposed that epithelial NO production could signal increased expression of IL-8 resulting in increased neutrophil infiltration into lungs. Our studies showed that exposure of H441 cells to increasing concentrations of NO donors markedly increased IL-8 mRNA and protein levels. NO dependent increases in IL-8 mRNA levels occurred independently of alterations in intracellular cGMP levels. The inductive effects of NO were exerted primarily at the posttranscriptional level via stabilization of IL-8 mRNA.

Selected Papers and Abstracts: