Year: 2016
Type: dissertation
Abstract: The respiratory epithelium constitutes the first line of defense against infectious agents that include pathogenic bacteria. These defenses are mediated via formation of a physical barrier constituting the tight junction proteins and a chemical barrier that consists of antimicrobial and inflammatory proteins. These early defenses that contribute to the innate immune response also contribute to maintenance of tissue homeostasis. Disturbance of the physical and the chemical barrier is used as a strategy by pathogenic microbes to evade the host immune system and establish a stable infection. Hence, strengthening these barriers by enhancing or modulating components of the innate immune response can serve as an important therapeutic strategy to prevent or treat infections. The unifying aim of this thesis dwells into investigations of factors and underlying mechanisms that may aid in strengthening the innate immune system by modulation of antimicrobial and inflammatory proteins. In paper І, we demonstrate that the short chain fatty acid derivate 4-phenyl butyric acid (PBA) enhances cathelicidin antimicrobial peptide (AMP) expression via the vitamin D receptor (VDR) in the human bronchial epithelial cell line VA10. PBA was shown to enhance pro-inflammatory responses in VA10 cells. Furthermore, the growth factor cytokines TGFα and TGFβ and associated receptor pathways differentially affect PBA induced cathelicidin expression. Co-treatment with PBA and vitamin D3 was shown to inhibit the growth of Pseudomonas aeruginosa in vitro and hence could have therapeutic potential to treat infections. In paper ІІ, we show that glucocorticoids that are commonly used as anti-inflammatory drugs down-regulate cathelicidin antimicrobial peptide expression in human monocytes and bronchial epithelial cells. Treatment with vitamin D3 counteracted this down-regulation. We further show that both dexamethasone and vitamin D3 act as anti-inflammatory agents in vitro and can be used in combination for therapeutic benefit. In paper ІІІ, we demonstrate that cyclic stretch that can be injurious mimics mechanical forces generated during ventilator induced lung injury causes down-regulation of cathelicidin expression in vitro in human bronchial epithelial cell lines. Treatment with AMP inducers vitamin D3 and/or PBA counteracted cyclic stretch mediated down-regulation of cathelicidin expression in our model and could be possible therapeutic benefits to prevent or treat infections. In paper ІV, we investigated the effects of adenylate cyclase (CyaA) toxin from Bordetella pertussis that causes whooping cough on innate immune responses in air-liquid interface differentiated VA10 cell line. CyaA toxin treatment caused barrier damaging effects, leading to disintegration of tight junction proteins, enhanced mucin secretion and differentially modulated antimicrobial peptides and inflammatory cytokines gene expression dependent on cyclic AMP signaling.
Source: Skemman
Author: Nikhil Nitin Kulkarni
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2623409227