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Rationale: Pathogenic T cells drive, or sustain, a number of inflammatory diseases. Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with the accumulation of activated T cells. We previously demonstrated that chronic cigarette smoke (CS) exposure causes oligoclonal expansion of lung CD4(+) T cells and CD8(+) T cells in a mouse model of COPD, thus implicating these cells in disease pathogenesis.Objectives: To determine whether T cells are pathogenic in a CS-induced mouse model of COPD.Methods: We transferred lung CD3(+) T cells from filtered air (FA)- and CS-exposed mice into Rag2(-/-) recipients. Endpoints associated with the COPD phenotype were then measured.Measurements and Main Results: Here, we demonstrate that chronic CS exposure generates pathogenic T cells. Transfer of CD3(+) T cells from the lungs of CS-exposed mice into Rag2(-/-) recipients led to substantial pulmonary changes pathognomonic of COPD. These changes included monocyte/macrophage and neutrophil accumulation, increased expression of cytokines and chemokines, activation of proteases, apoptosis of alveolar epithelial cells, matrix degradation, and airspace enlargement reminiscent of emphysema.Conclusions: These data formally demonstrate, for the first time, that chronic CS exposure leads to the generation of pathogenic T cells capable of inducing COPD-like disease in Rag2(-/-) mice. This report provides novel insights into COPD pathogenesis. [ABSTRACT FROM AUTHOR]

Rationale: Induced mainly by cigarette smoking, chronic obstructive pulmonary disease (COPD) is a global public health problem characterized by progressive difficulty in breathing and increased mucin production. Previously, we reported that acrolein levels found in COPD sputum could activate matrix metalloproteinase-9 (MMP9).Objectives: To determine whether acrolein increases expression and activity of MMP14, a critical membrane-bound endopeptidase that can initial a MMP-activation cascade.Methods: MMP14 activity and adduct formation were measured following direct acrolein treatment. MMP14 expression and activity was measured in human airway epithelial cells. MMP14 immunohistochemistry was performed with COPD tissue, and in acrolein- or tobacco-exposed mice.Measurements and Main Results: In a cell-free system, acrolein, in concentrations equal to those found in COPD sputum, directly adducted cysteine 319 in the MMP14 hemopexin-like domain and activated MMP14. In cells, acrolein increased MMP14 activity, which was inhibited by a proprotein convertase inhibitor, hexa-d-arginine. In the airway epithelium of COPD subjects, immunoreactive MMP14 protein increased. In mouse lung, acrolein or tobacco smoke increased lung MMP14 activity and protein. In cells, acrolein-induced MMP14 transcripts were inhibited by an epidermal growth factor receptor (EGFR) neutralizing antibody, EGFR kinase inhibitor, metalloproteinase inhibitor, or mitogen-activated protein kinase (MAPK) 3/2 or MAPK8 inhibitors, but not a MAPK14 inhibitor. Decreasing the MMP14 protein and activity in vitro by small interfering (si)RNA to MMP14 diminished the acrolein-induced MUC5AC transcripts. In acrolein-exposed mice or transgenic mice with lung-specific transforming growth factor-alpha (an EGFR ligand) expression, lung MMP14 and MUC5AC levels increased and these effects were inhibited by a EGFR inhibitor, erlotinib.Conclusions: Taken together, these findings implicate acrolein-induced MMP14 expression and activity in mucin production in COPD. [ABSTRACT FROM AUTHOR]

Mucins, which are complex glycoproteins that provide the viscoelastic properties of mucus that are essential for the protection of the airways, are characterized by a variable-number tandem repeats (VNTR) region that may undergo alternate splicing during transcription. Such transcripts may yield multiple proteins via diverse post-translational modifications involving glycosylation (within each VNTR). Fifteen distinct mucin genes have been identified, with several mapping to chromosomal clusters (ie, 7q22 and 11p15.5), possibly having evolved by gene duplication. The deduced protein sequences can be subdivided into both membrane-associated mucins and secreted mucins. Membrane-associated mucins consist of cytoplasmic, transmembrane, and extracellular domains. The membrane-associated mucins MUC1, MUC4, and MUC11 have been localized to the lung. In addition to VNTRs, secreted mucins possess repeated cysteine-rich D-domains (which are important in polymerization). Secreted mucins that are localized to the lung include MUC2 (in cells with and without secretory granules), MUC5AC (in surface and submucosal mucous cells), MUC5B and MUC8 (in submucosal mucous cells), and MUC7 (in submucosal serous cells). Currently, little is known about the regulation of mucins in COPD patients. Recent studies with acrolein and cigarette smoke have suggested that MUC5AC is inducible (accompanied by epidermal growth factor [EGF] ligand formation and the activation of EGF receptor-dependent pathways), whereas MUC5B is constitutively expressed (increasing through gland enlargement). Similarly, little is known about the genetic determinants that control mucus hypersecretion, but preliminary findings in animal models suggest that intrastrain differences in acrolein-induced mucin formation are amenable to genetic analysis. As our understanding of the functional genomics of mucin biology increases, further clinical targets and therapeutic strategies are likely to emerge. [ABSTRACT FROM AUTHOR]