The role of inducible nitric oxide synthase in macrophage activation following acute lung injury

• Main Author: Golden, Thea Noreen
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2016
• Subjects: Pharmacology; Surgery
• ISBN: 9781369605495; 1369605498

Macrophage origin and activity is complex in response to acute lung injury. Inducible nitric oxide synthase (iNOS) has a divergent role in the stages following intratracheal bleomycin mediated lung injury (ITB). We hypothesize iNOS is necessary for macrophage activation during the inflammatory and resolution phases that follow ITB. Further, recruited macrophages classically activate during inflammation and resident macrophages alternatively activate during resolution. To test these hypotheses, iNOS was manipulated via scavenge of products, systemic selective iNOS inhibition and chimeric mice in which particular populations were NOS2-/-. C57/BL6 mice were intratracheally instilled with bleomycin and samples collected 8 and 15 days following instillation. This work identified oxidants to promote inflammation during the early stages following ITB. Systemic iNOS inhibition reduced classical activation of recruited macrophages during inflammation and alternative activation of recruited macrophages during resolution. Resident macrophage alternative activation was not dependent on iNOS activity. Chimeric mice demonstrated iNOS of a particular cell population is necessary for macrophage activation. Classical activation of recruited cells is dependent on recruited cell iNOS. Early alternative activation is promoted when recruited macrophages were iNOS incompetent. A pulmonary source of iNOS plays a role in alternative activation during resolution. This work has demonstrated iNOS is important to classical and alternative activation of macrophages. The cell population expressing iNOS determines the effect on activation. The complexity of macrophage populations and effect of iNOS activity on macrophage activation furthers our understanding of the response to ITB and adapted therapeutic approaches have potential for clinical improvement.