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.

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.
. Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent.
J. Immunol.
Zhang, X., P. Shan, G. Jiang, L. Cohn, P. J. Lee.
. Toll-like receptor 4 deficiency causes pulmonary emphysema.
J. Clin. Invest.
Maes, T., K. R. Bracke, K. Y. Vermaelen, I. K. Demedts, G. F. Joos, R. A. Pauwels, G. G. Brusselle.
. Murine TLR4 is implicated in cigarette smoke-induced pulmonary inflammation.
Int. Arch. Allergy Immunol.