In their article, Doz et al. (1) investigate the role of TLR4/MyD88 and IL-1R1/MyD88 signaling in cigarette smoke (CS)-induced pulmonary inflammation to unravel mechanisms involved in the development of chronic obstructive pulmonary disease (COPD). In an acute CS exposure model of 3 days, they demonstrate a reduced CS-induced influx of neutrophils in bronchoalveolar lavage (BAL) fluid in TLR4−/−, MyD88−/−, and IL-R1−/− mice compared with C57BL/6 controls, as well as reduced IL-1, IL-6, and KC levels and reduced matrix metalloproteinase-9 activity in BAL. In contrast, TLR4−/− (C57BL/6J, C57BL/10ScNJ, or C3H/HeJ background) and MyD88−/− animals appear to develop spontaneous age-related emphysema, which is not associated with an inflammatory response in BAL or lung tissue (2).

We demonstrated (3) that subacute CS exposure for 5 wk in TLR4-defective animals (C3H/HeJ) results in a reduced pulmonary accumulation of neutrophils, lymphocytes, and dendritic cells in BAL as well as lower levels of MCP-1 and TNF-α compared with wild-type (C3H/HeOuJ) animals. However, after chronic cigarette smoke exposure for 26 wk TLR4 became of less importance, with only minor differences in pulmonary inflammation between the two strains, similar MCP-1 and TNF-α levels in BAL, and similar matrix metalloproteinase-12 expression in the lung.

These studies highlight the complexity of the pathogenic mechanisms in COPD and emphysema, because CS-induced pulmonary inflammation is TLR4-dependent in (sub) acute experiments (1) whereas it is TLR4-independent in chronic experiments (3).

In conclusion, these papers underscore the importance of both acute and chronic models in unraveling the pathogenesis of COPD.

1
Doz, E., N. Noulin, E. Boichot, I. Guénon, L. Fick, M. Le Bert, V. Lagente, B. Ryffel, B. Schnyder, V. F. J. Quesniaux, I. Couillin.
2008
. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent.
J. Immunol.
180
:
1169
-1178.
2
Zhang, X., P. Shan, G. Jiang, L. Cohn, P. J. Lee.
2006
. Toll-like receptor 4 deficiency causes pulmonary emphysema.
J. Clin. Invest.
116
:
3050
-3059.
3
Maes, T., K. R. Bracke, K. Y. Vermaelen, I. K. Demedts, G. F. Joos, R. A. Pauwels, G. G. Brusselle.
2006
. Murine TLR4 is implicated in cigarette smoke-induced pulmonary inflammation.
Int. Arch. Allergy Immunol.
141
:
354
-368.