Editorial: Neutrophil elastase and the lung: is it degradation, repair, emphysema, or fibrosis? What tilts it left or right?

Until not so long ago, proteases were considered to be mere scissors, with the ECM as their main target, either for degradative or remodeling purposes. However, it is becoming obvious that protease actions are not limited to ECM degradation. Indeed, cells themselves have been shown to be targets of proteases, and PARs have proven to be an important family of cell membrane receptors through which proteolytic enzymes may exert some of their activities [1]. In the mid-1960s, the seminal work of the Laurell and Eriksson group [2] indirectly identified proteases as likely culprits in the pathogenesis of the genetic form of emphysema (e.g., "ZZ emphysema") and suggested that antiproteinases, such as A1Pi (and others), could be of therapeutic use in that pathology. Rodent models of protease instillation indeed subsequently confirmed that when compared with lung homeostasis (Fig. 1A), proteases can induce emphysemateous lesions (Fig. 1B) [3]. These important breakthroughs led to the theory of "protease-antiprotease imbalance," now widely applied to other diseases, including other chronic lung diseases (see below). One of the most important proteases involved in that process was identified as NE, a protease later identified as an antimicrobial mediator at homeostasis [4] and whose function was redefined more recently at the molecular level [5]. Irrespectively, in the late 1980s/early 1990s, pathologists started recognizing that the emphysemateous lung was by no means homogenous and that within the same lung, areas of remodeling/fibrosis could coexist with air space-enlarged areas, one of the cardinal features of emphysema [6, 7]. This suggested that the definition of this condition, put forward by the National Heart, Lung, and Blood Institute in 1984 as "a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and without obvious fibrosis," may have been misleading. The paper, by Gregory et al. [8], published in this issue of the Journal of Leukocyte Biology, adds credence to the possibility that NE, traditionally known as an "emphysema/chronic obstructive pulmonary disease inducer" (causing alveolar-wall damage in the peripheral lung and increasing mucus production in the airways), may, under certain conditions, also yield a fibrotic phenotype and may potentially participate in the generation of full-blown IPF. There is certainly no shortage of neutrophils, the main (or only) source of NE in IPF, and previous studies have shown that SLPI, an important mucosal inhibitor of NE, was protective in a hamster model of bleomycin-induced fibrosis [9]. With the use of a similar bleomycin model, Chua et al. [10] showed that NE mice were protected when compared with WT mice, and they found reduced tissue levels of TGF-b, an important repair/fibrogenic cytokine. Gregory et al. [8] convincingly show in the present manuscript that NE can, at nanomolar concentrations, induce fibroblast proliferation, promote wound closure of a fibroblast cell layer in vitro, and induce myofibroblast differentiation (Fig. 1C). In vivo, with the use of a different model than the one mentioned above (i.e., asbestos-mediated instead of bleomycin-mediated fibrosis), these authors also demonstrate lesser fibrotic lesions in NE mice when compared with WT mice. Mechanistically, the authors demonstrate that NE acts partly through cleaving IRS-1, activating the PI3K/AKT pathway, events leading to fibroblast proliferation (Fig. 1D). By contrast, the mechanisms underlying NE-induced myofibroblast differentiation were not fully deciphered in the present study and were shown to be mothers against decapentaplegic homolog 3 dependent (SMAD-3) but TGF-b independent. Although the current study does not rule out the involvement of cell-surface