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We obviously agree with Porter1 on the need to make a distinction between egression of infiltrated leucocytes across mucosal epithelia, where a swift further elimination of the lumen cells can be expected to occur (nasal, tracheobronchial, gut, bladder), and the bronchiolar–alveolar epithelial linings where there is a risk of undesirable accumulation of lumen cells. We repeat this cautionary note in an extended review on resolution of cell-mediated respiratory diseases where we discuss a role of egression in the elimination not only of granulocytes and lymphocytes but also of mast cells and dendritic cells.2 We further discuss how elimination of leucocytes through egression can be compatible with the use of sputum cell counts to adjust treatment in asthma.1 The concept developed in our two reviews is underpinned foremost by clinical observations and experimental findings in patients. We were indeed surprised to find that numerous, human, so far little understood, in vivo data supported the resolving role of transepithelial egression whereas little support for the role of leucocyte apoptosis, the accepted paradigm, emerged. However, Porter's comments mainly concern mouse model findings. Of interest are supporting findings in murine (mouse and rat) models of ‘asthma’ indicating that inhibition of egression can have serious respiratory consequences. We are aware of severe limitations of mouse models3 but felt that these data should be discussed. We also speculated that cell traffic in mouse airways, better than cell activation, could be relevant. However, the distinction between bronchial and alveolar cell traffic, that Porter highlights, may not be readily made in mice. In sharp contrast to humans, mice lack a bronchial circulation. The dominance of the pulmonary circulation is reflected in the work carried out by Corry et al. These authors repeatedly emphasise that their studies concern parenchymal leucocytes. When egression is inhibited, leucocytes accumulate in pulmonary parenchymal tissues ‘causing’ severely impeded gas exchange.4 Oxygen is an effective remedy in these lethally affected mice.3 Corry et al3 particularly underscore that ‘differences in smooth muscle or other contractile cell function cannot explain the increased mortality observed.’ Hence, Porter's statement that death in this model is by ‘bronchoconstriction’ is puzzling. Then Porter discusses data suggesting that mouse lung injury evoked by intratracheal bleomycin is caused by transepithelial neutrophil egression. We are not equally convinced. For example, n-formyl-neoleucyl-leucyl-phenylalanine (nFNLP) may not be used as a specific inducer of neutrophil egression, as quoted by Porter. nFNLP-like peptides are multipotent agents and avidly induce neutrophil toxicity as well.
Nearly 130 years have passed since Julius Cohnheim held classic lectures on inflammation.5 He discussed the resolution of inflammatory infiltrates in mucosally lined organs, specifically noting the advantageous outward transport available to bronchi and lung alveoli. Cohnheim's contemporary and perpetual authority, Henry Hyde Salter, observed cell-rich sputum production at resolution of severe asthma. Salter intriguingly analysed how the most peripheral airways could be cleared of cellular exudates since coughing would have little impact here.6 It seems overdue to fill in the large gaps in our knowledge concerning clearance of cells from the human bronchiolar–alveolar lumen.
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