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In Utero Exposure to Second-Hand Smoke Aggravates Adult Responses to Inhaled Irritants Rui Xiao Louisiana State University and Agricultural and Mechanical College

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In Utero Exposure to Second-Hand Smoke Aggravates Adult Responses to Inhaled Irritants Rui Xiao Louisiana State University and Agricultural and Mechanical College Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2014 In Utero Exposure To Second-Hand Smoke Aggravates Adult Responses To Inhaled Irritants Rui Xiao Louisiana State University and Agricultural and Mechanical College Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Medicine and Health Sciences Commons Recommended Citation Xiao, Rui, "In Utero Exposure To Second-Hand Smoke Aggravates Adult Responses To Inhaled Irritants" (2014). LSU Doctoral Dissertations. 3345. https://digitalcommons.lsu.edu/gradschool_dissertations/3345 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. IN UTERO EXPOSURE TO SECOND-HAND SMOKE AGGRAVATES ADULT RESPONSES TO INHALED IRRITANTS A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Comparative Biomedical Sciences by Rui Xiao B. S., Shanghai Jiao Tong University, 2008 May 2014 ACKNOWLEDGEMENTS The entire faculty and office staff in the CBS Department of the LSU SVM have been extremely helpful to my educational experience at LSU. Inside our laboratory, like a warm family, there have been a number of people who contributed greatly to the work described within this manuscript and each one deserves acknowledgement and recognition for their effort-- -Zakia Perveen, Lindsey Clemones, Lisa Earl, Dr. Alexandra Noel and Dr. Md Hasanuzzaman. Within the School of Veterinary Medicine, Dr. Daniel Paulsen and Dr. Viviana Le Donne, from the PBS Department, provided their histopathology expertise for the project while Dr. Rodney Rouse, formerly of CBS, now of the US Food Drug Administration, laid down the research foundation of in utero smoke exposures and ovalbumin challenge protocol, which are essential to the success of these studies. We also had help from further outside collaborators, including Paula Polk (LSUHSC-Shreveport) with microarray processing and Dr. Namasivayam Ambalavanan (UAB) with lung morphometric analysis. Thanks also go to my committee members, including Dr. David Horohov, Dr. Shisheng Li, Dr. Kevin Kleinow and Dr. Craig Hart (Dean’s Representative), for their time serving on my committee as well as their helpful advice over the years. Finally, I would like to express my deepest gratitude to my major advisor Dr. Arthur Penn, who has generously offered me his time, knowledge and resources. Along the last few years, he has taught me so much about scientific research as well as the American culture and has given me numerous opportunities to work on interesting projects and present new findings at research conferences. Without his support and guidance, these projects and myself would not have come this far. I am proud to call him a great mentor and a dear friend. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ........................................................................................................ ii LIST OF TABLES ...................................................................................................................... v LIST OF FIGURES .................................................................................................................... vi LIST OF ABBREVIATIONS .................................................................................................. viii ABSTRACT …… ...................................................................................................................... ix CHAPTER 1. LITERATURE REVIEW ..................................................................................... 1 1.1 Short-term and Long-term Effects of Air Pollutants ...........................................................1 1.2 Early Onset of Adult Respiratory Diseases ........................................................................4 1.3 In Utero Smoke Exposure Studies and the Current Experimental Design ...........................9 CHAPTER 2. IN UTERO EXPOSURE TO SECOND-HAND SMOKE AGGRAVATES ADULT RESPONSES TO IRRITANTS: ADULT SECOND-HAND SMOKE ... 12 2.1 Introduction .................................................................................................................... 12 2.2 Materials and Methods .................................................................................................... 13 2.3 Results ............................................................................................................................ 18 2.4 Discussion....................................................................................................................... 30 CHAPTER 3. IN UTERO EXPOSURE TO SECOND-HAND SMOKE AGGRAVATES ADULT RESPONSES TO IRRITANTS: ADULT OVALBUMIN...................... 37 3.1 Introduction .................................................................................................................... 37 3.2 Materials and Methods .................................................................................................... 38 3.3 Results ............................................................................................................................ 42 3.4 Discussion....................................................................................................................... 53 CHAPTER 4. IN UTERO EXPOSURE TO SECOND-HAND SMOKE ACTIVATES ONCOGENIC MICRORNAS IN OVALBUMIN-CHALLENGED ADULT MICE.................................................................................................................... 59 4.1 Introduction .................................................................................................................... 59 4.2 Materials and Methods .................................................................................................... 61 4.3 Results ............................................................................................................................ 63 4.4 Discussion....................................................................................................................... 69 4.5 Conclusion ...................................................................................................................... 74 CHAPTER 5. CONCLUDING REMARKS .............................................................................. 75 5.1 Benefits from New Technology Implemented in the Present Study .................................. 75 5.2 Research Summary ......................................................................................................... 80 5.3 Critical Thoughts for Future Studies ................................................................................ 81 REFERENCES ......................................................................................................................... 82 iii APPENDIX. REPRINT PERMISSION FROM AMERICAN THORACIC SOCIETY. ............ 97 VITA……………. .................................................................................................................... 99 iv LIST OF TABLES Table 1–1. Decreases in concentrations of common pollutants indicated that air quality has improved nationally since 1980 (EPA.gov). ................................................................................. 3 Table 2–1. In utero SHS exposure identified genes primarily associated with immune system processes. .................................................................................................................................. 24 Table 2–2. The most striking KEGG pathways of adult exposure-affected genes are “Circadian rhythm–mammal”, “MAPK signaling pathway” and “Pathways in cancer”. .............. 24 Table 3–1. There were no significant differences between SHS- and AIR-exposed mice, regarding percent linear mucosa occupied by goblet cells and presence/absence of goblet cells, in the distal 2 generations of bronchioles in the peripheral lung. ................................................. 44 Table 3–2. All 113 differentially expressed genes between SHS-OVA and AIR-OVA groups, shown in Figure 3-5A, are listed with additional information. .................................................... 46 Table 3–3. Ingenuity Pathway Analysis results indicated that the differentially expressed genes affected by in utero SHS exposure are significantly associated with inflammatory responses, cancer and respiratory disease, and also are involved in IL-17-associated pathways. .. 51 Table 4–1. In utero exposure to SHS potentiates AHR, elevated BALF cytokine production and altered lung gene expression in OVA-challenged adult mice. ............................................... 61 Table 4–2. In utero SHS exposure dysregulates miRNAs that are associated with lung cancer and inflammation....................................................................................................................... 70 Table 4–3. According to multiple sources, sixteen tumor suppressor genes are predicted targets of the 3 oncomirs, miR-155, miR-21, and miR-18a, and show anti-correlation with oncomir expression. ................................................................................................................... 73 Table 5–1. The qRT-PCR results confirmed the differential expression of eight
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