Comment on “An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness”

Abstract

Increased airway hyperresponsiveness and epithelial remodeling in asthmatic LTA 4 H-KO mice may be mediated by CysLTs rather than elevated tripeptide PGP.The recent article by Patel et al.(1) characterizes the biological response of an allergic pulmonary inflammation on the background of leukotriene A 4 hydrolase (LTA 4 H)-deficient mice. The authors demonstrate that, although many parameters of inflammation were reduced in the absence of LTA 4 H, the mice exhibited increased airway resistance, airway remodeling, and goblet cell activation.Work from this group previously suggested that accumulation of the tripeptide proline-glycine-proline (PGP) in the absence of LTA 4 H would lead to enhanced neutrophilic inflammation in models of pulmonary infection (2, 3); in this model of sterile allergic inflammation, however, no such enhanced neutrophilic inflammation could be observed. Our recent publication demonstrated that PGP is actually not chemotactic for neutrophils in LTA 4 H knockout (KO) mice nor in human cells and provides an explanation for the observations by Patel et al. on neutrophils in this sterile inflammatory setting (4). Therefore, our conclusion was that the enhanced neutrophil response previously observed in infection models is likely a compensatory immune response to the infection in the absence of LTA 4 H rather than driven by PGP elevation.Similarly, we believe that the observations on airway hyperresponsiveness and epithelial remodeling in this recent article by Patel et al. may not be due to the elevation of the PGP peptide but could actually be caused by the effects of the cysteinyl leukotrienes (CysLTs) in asthma, which are known to induce bronchoconstriction, airway remodeling, goblet cell activation, and mucus production (5). It is well known that inhibition of specific enzymes of the arachidonic acid pathway can lead to the elevation of lipid mediators due to pathway shunting. We have observed that absence of LTA 4 H can lead to the elevation of CysLTs after stimulation of immune cells in vitro or in inflammatory settings in vivo in LTA 4 H KO mice ( Fig.

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“…It is well-known that inhibition of specific enzymes of the arachidonic pathway can lead to the elevation of lipid mediators due to pathway shunting. Such metabolic pathway switching in eicosanoid family has previously been described in vitro and in vivo as the absence of LTA4H can lead to the elevation of CysLT [ 28 ]. The involvement of MGSTs in CysLT secretion by MDA-B02 cell was further confirmed in the culture media of cells incubated in presence of arachidonic acid (AA), the precursor of all eicosanoids, and treated with A23187, a calcium ionophore well-known to promote CysLT synthesis ( Figure 2 E).…”

Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A4 Hydrolase

“…Therefore, selective inhibition of the biosynthesis of pro-inflammatory LTB 4 with simultaneous clearance of PGP by LTA 4 H would contribute to the resolution of inflammation. Moreover, the inhibition of LTA 4 H results in unused LTA 4 which may potentially increase conversion to cysteinylleukotrienes [16], or pro-resolving mediators, such as lipoxins and resolvins [17,18].…”