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SUMMARY:A single intratracheal dose of porcine pancreatic elastase, which is cleared from the lung by 24 hours, was administered to wild-type, IL-1␤ type 1 receptor-deficient, double TNF-␣ (type 1 and type 2) receptor-deficient, and combined TNF-␣ (type 1 receptor) plus IL-1␤ receptor-deficient mice. The mean linear intercept (Lm) of saline-treated mice was 32(3) m [mean(SE)]. For wild-type elastase-treated mice, Lm was 81(6) m at 21 days versus 52(5) m at 5 days after treatment, indicating that alveolar wall remodeling occurs long after the elastase injury. At 21 days, Lm values were 67(10), 62(3), and 39(5) m in elastase-treated mice deficient in the IL-1␤ receptor, double TNF-␣ receptors, and combined receptors, respectively. The level of apoptosis assessed by a terminal deoxynucleotidyl transferase-catalyzed in situ nick end-labeling assay was increased at 5 days after elastase treatment and was markedly and similarly attenuated in the IL-1␤, the double TNF-␣, and the combined receptor-deficient mice. Our results indicate that inflammatory mediators exacerbate elastase-induced emphysema. We estimate that in the combined TNF-␣ ϩ IL-1␤ receptor-deficient mice, inflammation accounts for about 80% of the emphysema that develops after elastase treatment; decreased apoptosis of lung cells likely contributes to decreased severity of emphysema. (Lab Invest 2002, 82:79 -85). P ulmonary emphysema is defined as abnormal enlargement of respiratory spaces with destruction of the alveolar walls. Experimental evidence supports the concept that alveolar units are damaged when activated macrophages and neutrophils elaborate proteases that degrade elastin and other structural proteins.The proinflammatory cytokines IL-1␤ and TNF-␣ are released during inflammatory reactions induced by infection or injury. These effecter substances have overlapping biologic functions, suggesting that they share some common signal transduction pathways (Dinarello, 1997;Kusano et al, 1998;Ledgerwood et al, 1999;Muegge et al, 1989; O' Neill and Greene, 1998;Stewart and Marsden, 1995).In experimental animals, IL-1␤ stimulates several components of the acute-phase response. The cytokine stimulates the expression of metalloproteinase and other enzymes involved in the degradation of connective tissue proteins (Kusano et al, 1998), and it also stimulates apoptosis (Dinarello, 1998). IL-1␤ utilizes a single signaling receptor to activate two IL-1 receptor-associated kinases (IRAK-1 and IRAK-2), to recruit TNF receptor-associated factor 6 (TRAF6) and activate nuclear factor-B (NF-B) (Cao et al, 1996). Activation of NF-B results in nuclear translocation and alterations in the rate of transcription of certain target genes (Baldwin, 1996;Gilmore, 1999). NF-B also either increases or decreases apoptosis depending on the cell type (Barkett and Gilmore, 1999). IL-1␤ affects gene transcription via several other transacting factors including transcription factor AP-1 proteins and CCAAT-enhancer binding proteins (C/EBP) (Muegge et al, 1989;Osborn et al, 1989).TNF...

Desmosine (DES) and isodesmosine (IDES) are two unusual, tetrafunctional, pyridinium ring-containing amino acids involved in elastin cross-linking. Being amino acids unique to mature, cross-linked elastin, they are useful for discriminating peptides derived from elastin breakdown from precursor elastin peptides. According to these features, DES and IDES have been extensively discussed as potentially attractive indicators of elevated lung elastic fibre turnover and markers of the effectiveness of agents with the potential to reduce elastin breakdown. In the present manuscript, immunology-based and separation methods for the evaluation of DES and IDES are discussed, along with studies reporting increased levels of urine excretion in chronic obstructive pulmonary disease (COPD) patients with and without a 1 -antitrypsin deficiency. The results of the application of DES and IDES as surrogate end-points in early clinical trials in COPD are also reported. Finally, recent advances in detection techniques, including liquid chromatography tandem mass spectrometry and high-performance capillary electrophoresis with laser-induced fluorescence, are discussed. These techniques allow detection of DES and IDES at very low concentration in body fluids other than urine, such as plasma or sputum, and will help the understanding of whether DES and IDES are potentially useful in monitoring therapeutic intervention in COPD.

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