The Role of Interleukin-1β in Murine Cigarette Smoke-induced Emphysema and Small Airway Remodeling

被引:169
作者
Churg, Andrew [1 ]
Zhou, Steven [1 ]
Wang, Xiaoshan [1 ]
Wang, Rona [1 ]
Wright, Joanne L. [1 ]
机构
[1] Univ British Columbia, Dept Pathol, Vancouver, BC V6T 2B5, Canada
基金
加拿大健康研究院;
关键词
IL-1; beta; TNF-alpha; cigarette smoke; emphysema; apoptosis; NECROSIS-FACTOR-ALPHA; OBSTRUCTIVE PULMONARY-DISEASE; CONNECTIVE-TISSUE BREAKDOWN; MACROPHAGE METALLOELASTASE; INDUCED INFLAMMATION; CELL APOPTOSIS; LUNG; IL-1-BETA; EXPRESSION; BETA;
D O I
10.1165/rcmb.2008-0038OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Interleukin-1 beta (IL-1 beta), a proinflammatory cytokine, is elevated in cigarette smokers. To determine whether IL-1 beta plays a role in the pathogenesis of cigarette smoke-induced emphysema and small airway remodeling, IL-1 receptor knockout (IL1RKO), TNF-alpha receptor knockout (TNFRKO), or C57BI/6 (control) mice were exposed to cigarette smoke acutely or for up to 6 months. With a single acute exposure, smoke elevated IL-1 beta in C57BI/6 mice. IL1RKO mice were protected against acute smoke-mediated increases in lavage inflammatory cells and matrix breakdown. In C57BI/6 mice, acute smoke-mediated increases in inflammatory cells, serum IL-1 beta, and serum TNF-alpha were blocked by z-VAD-fmk, a pan-caspase inhibitor, or z-WEHD-fmk, a caspase-1 (IL-1-converting enzyme, [ICE]) inhibitor. With 6 months of exposure, IL-1 beta was no longer increased, but IL-18 was elevated. After 6 months of exposure, IL1RKO mice were 65% protected against emphysema, whereas TNFRKO mice were 83% protected. Both strains were completely protected against small airway remodeling. Lavage desmosine, hydroxylproline, and hyaluronan, matrix breakdown markers, were elevated in C57 but not IL1RKO mice. We conclude that IL-1 beta plays a significant role in induction of murine emphysema and small airway remodeling, and is comparable to TNF-alpha in its effects. The protective effects of caspase inhibitors appear to be related to inhibition of ICE and raise the question of whether models that ameliorate emphysema with caspase inhibitors are really blocking IL-1 beta (and IL-18) activation rather than blocking apoptosis.
引用
收藏
页码:482 / 490
页数:9
相关论文
共 48 条
  • [1] Alveolar wall apoptosis causes lung destruction and emphysematous changes
    Aoshiba, K
    Yokohori, N
    Nagai, A
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2003, 28 (05) : 555 - 562
  • [2] Chronic obstructive pulmonary disease: molecular and cellular mechanisms
    Barnes, PJ
    Shapiro, SD
    Pauwels, RA
    [J]. EUROPEAN RESPIRATORY JOURNAL, 2003, 22 (04) : 672 - 688
  • [3] TGF-β and Smad3 signaling link inflammation to chronic fibrogenesis
    Bonniaud, P
    Margetts, PJ
    Ask, K
    Flanders, K
    Gauldie, J
    Kolb, M
    [J]. JOURNAL OF IMMUNOLOGY, 2005, 175 (08) : 5390 - 5395
  • [4] Cytokines as targets in chronic obstructive pulmonary disease
    Chung, K. F.
    [J]. CURRENT DRUG TARGETS, 2006, 7 (06) : 675 - 681
  • [5] Tumor necrosis factor-α drives 70% of cigarette smoke-induced emphysema in the mouse
    Churg, A
    Wang, RD
    Tai, H
    Wang, XS
    Xie, CS
    Wright, JL
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2004, 170 (05) : 492 - 498
  • [6] Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-α release
    Churg, A
    Wang, RD
    Tai, H
    Wang, XS
    Xie, CS
    Dai, J
    Shapiro, SD
    Wright, JL
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2003, 167 (08) : 1083 - 1089
  • [7] Tumor necrosis factor-α is central to acute cigarette smoke-induced inflammation and connective tissue breakdown
    Churg, A
    Dai, J
    Tai, H
    Xie, CS
    Wright, JL
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2002, 166 (06) : 849 - 854
  • [8] Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice
    Churg, A
    Zay, K
    Shay, S
    Xie, CS
    Shapiro, SD
    Hendricks, R
    Wright, JL
    [J]. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2002, 27 (03) : 368 - 374
  • [9] CHURG A, 2008, AM J RESP CRIT CARE, V177, pA866
  • [10] Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs
    Churg, Andrew
    Wang, Rona
    Wang, Xiaoshan
    Onnervik, Per-Ola
    Thim, Kerstin
    Wright, Joanne L.
    [J]. THORAX, 2007, 62 (08) : 706 - 713