CD8+ T Cells Are Required for Inflammation and Destruction in Cigarette Smoke-Induced Emphysema in Mice

Abstract

Increased numbers of T lymphocytes are observed in the lungs of patients with chronic obstructive pulmonary disease, but their role in the disease process is not known. We investigated the role of CD8+ T cells in inflammatory cell recruitment and lung destruction in a cigarette smoke-induced murine model of emphysema. In contrast to wild-type C57BL/6J mice that displayed macrophage, lymphocyte, and neutrophil recruitment to the lung followed by emphysema in response to cigarette smoke, CD8+ T cell-deficient (CD8−/−) mice had a blunted inflammatory response and did not develop emphysema when exposed to long-term cigarette smoke. Further studies supported a pathogenetic pathway whereby the CD8+ T cell product, IFN-γ-inducible protein-10, induces production of macrophage elastase (matrix metalloproteinase 12) that degrades elastin, both causing lung destruction directly and generating elastin fragments that serve as monocyte chemokines augmenting macrophage-mediated lung destruction. These studies demonstrate a requirement for CD8+ T cells for the development of cigarette smoke-induced emphysema and they provide a unifying pathway whereby CD8+ T cells are a central regulator of the inflammatory network in chronic obstructive pulmonary disease.

Pulmonary Emphysema Induced by Cigarette Smoke Solution and Lipopolysaccharide in Guinea Pigs

“…[17][18][19][20][21][22][23][24] When using the older methodology, it takes more than 3 months to induce emphysema. Therefore, we anticipated that the intratracheal instillation employed in this experiment would deliver the highest possible fraction of an instillation to the lower airways.…”

“…By exposing animals to 3 or more months of cigarette smoke, various experimental COPD models have been developed in guinea pigs, rats and mice. [17][18][19][20][21][22][23][24] Although all of these models have emphysematous airspace enlargement, studies on the clinical pathogenesis of COPD would be much more efficient if the emphysematous condition could be experimentally reproduced within a much shorter time period.In order to shorten the period of development of an experimental COPD model, a more efficient delivery system of the constituents of cigarette smoke into the lung is required. To bypass the problem of using inhaled smoke, which is spontaneously exhaled, we attempted to intratracheally instill a cigarette smoke solution (CSS) over several weeks.…”

Role of T-lymphocytes and pro-inflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease

“…The potential for activated T-cells to cause lung injury in mice was evidenced after adoptive transfer of CD8 + T-cells with specifi cities for neoantigens that were expressed on alveolar epithelial cells (Enelow et al 1998). CD8 + T-lymphocytes were also recently shown to be critical for the induction of infl ammation and tissue destruction in a murine model of smoke-induced emphysema (Maeno et al 2007). In addition, adoptive transfers of syngeneic CD4 + lymphocytes that had been sensitized to endothelial cell antigens resulted in development of emphysema in naïve rats, thus highlighting the potential for CD4 + T-cell associated autoimmune disease processes in COPD (Taraseviciene-Stewart et al 2005).…”

Chemokine receptor CXCR3 is important for lung tissue damage and airway remodeling induced by short-term exposure to cigarette smoking in mice

“…To evaluate the difference in enlargement of alveolar spaces between CXCR3-/-mice and WT mice after short-term CS insult, we measured the linear intercept, Lm, which reflects the average distance between alveolar walls and parallels the degree of emphysema [12] .…”

“…Accumulating evidence has suggested that CXCR3-CXCL10 interactions play a pivotal role in the inception and progression of COPD via recruitment of CD8+ T cells into airways and lung parenchyma [12,13] . CXCR3 and its specific ligand CXCL10/interferon-inducible protein-10 (IP-10) were abundantly expressed in bronchiolar epithelial cells and airway smooth muscle cells.…”