Abstract
BackgroundBronchioles are critical zones in cigarette smoke (CS)-induced lung inflammation. However, there have been few studies on the in vivo dynamics of cytokine gene expression in bronchiolar epithelial cells in response to CS.MethodsWe subjected C57BL/6J mice to CS (whole body exposure, 90 min/day) for various periods, and used laser capture microdissection to isolate bronchiolar epithelial cells for analysis of mRNA by quantitative reverse transcription-polymerase chain reaction.ResultsWe detected enhanced expression of keratinocyte-derived chemokine (KC), macrophage inflammatory protein-2 (MIP-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) by bronchial epithelial cells after 10 consecutive days of CS exposure. This was mirrored by increases in neutrophils and KC, MIP-2, TNF-α, and IL-1β proteins in the bronchoalveolar lavage (BAL) fluid. The initial inhalation of CS resulted in rapid and robust upregulation of KC and MIP-2 with concomitant DNA oxidation within 1 hr, followed by a return to control values within 3 hrs. In contrast, after CS exposure for 10 days, this initial surge was not observed. As the CS exposure was extended to 4, 12, 18 and 24 weeks, the bronchiolar KC and MIP-2 expression and their levels in BAL fluid were relatively dampened compared to those at 10 days. However, neutrophils in BAL fluid continuously increased up to 24 weeks, suggesting that neutrophil accumulation as a result of long-term CS exposure became independent of KC and MIP-2.ConclusionThese findings indicate variable patterns of bronchiolar epithelial cytokine expression depending on the duration of CS exposure, and that complex mechanisms govern bronchiolar molecular dynamics in vivo.
Highlights
Bronchioles are critical zones in cigarette smoke (CS)-induced lung inflammation
Macrophages, and lymphocytes in the airways are found associated with Chronic obstructive pulmonary disease (COPD) [1,2,3], and various mediators derived from these cells, such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP-1), and matrix metalloproteinase (MMP)-2, MMP-8, and MMP-9, are suggested to contribute to the development of COPD [4,5]
Whole lung and bronchiolar cytokine expression during 10 days of CS exposure Since CS produced oxidative stress in the airways (Figure 2), we examined whether bronchiolar epithelial cells express cytokines in response to CS by real-time RT-PCR analyses of RNA isolated from Laser Capture Microdissection (LCM)-retrieved terminal bronchiolar epithelial cells
Summary
Bronchioles are critical zones in cigarette smoke (CS)-induced lung inflammation. There have been few studies on the in vivo dynamics of cytokine gene expression in bronchiolar epithelial cells in response to CS. Cigarette smoke (CS) is the main risk factor for the development of COPD. Oxidative stress caused by CS can injure lung cells directly and can trigger cytokine production, leading to the recruitment of inflammatory cells into the lungs [6,7,8]. The induction of these cytokines is regulated by the activation of redox-sensitive transcription factors, such as nuclear factor-kappa B (NF-κB) [9,10]. Increased expression of NF-κB has been detected in the airway epithelium of smokers compared to non-smokers [11]
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