Lysyl oxidase (LOX)3 catalyzes the oxidation of specific lysine residues within extracellular elastin and collagen thus generating residues of ␣-aminoadipic-␦-semialdehyde within these proteins (1). These peptidyl aldehydes can then undergo condensation with vicinal ␣-aminoadipic-␦-semialdehyde or unmodified lysine residues to form inter-and intrapeptide covalent cross-linkages that stabilize these fibrous proteins. In addition to the non-ionic aldehyde product, the LOX-catalyzed reaction acting on protonated lysine produces stoichiometric amounts of hydrogen peroxide and ammonium, as shown in Reaction 1.

Elastase/anti-elastase imbalance is a hallmark of emphysema, a chronic obstructive pulmonary disease associated with the rupture and inefficient repair of interstitial elastin. We report that neutrophil elastase (

Previously, we have demonstrated that basic fibroblast growth factor (bFGF) decreases elastin gene transcription in confluent rat lung fibroblasts via the binding of a Fra-1-c-Jun heterodimer to an activator protein-1-cAMP response element in the distal region of the elastin promoter. In the present study, we show that bFGF activates the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2, resulting in the translocation of phosphorylated extracellular signal-regulated kinase 1/2 into the nucleus followed by increased binding of Elk-1 to the serum response element of the c-Fos promoter, transient induction of c-Fos mRNA, and sustained induction of Fra-1 mRNA. The addition of PD-98059, an inhibitor of mitogen-activated protein kinase kinase, abrogates the bFGF-dependent repression of elastin mRNA expression. Comparative analyses of confluent and subconfluent fibroblast cultures reveal significant differences in elastin mRNA levels and activator protein-1 protein factors involved in the regulation of elastin transcription. These findings suggest that bFGF modulates specific cellular events that are dependent on the state of the cell and provide a rationale for the differential responses that can be expected in development and injury or repair situations.

. Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-␤ on tropoelastin mRNA in lung fibroblasts.