D'Armiento J.M.,Columbia University |
Goldklang M.P.,Columbia University |
Hardigan A.A.,St Lukes Roosevelt Health Science Center |
Geraghty P.,St Lukes Roosevelt Health Science Center |
And 9 more authors.
Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al. Source
Geraghty P.,St Lukes Roosevelt Health Science Center |
Wyman A.E.,St Lukes Roosevelt Health Science Center |
Wyman A.E.,University of Maryland, Baltimore |
Garcia-Arcos I.,Columbia University |
And 4 more authors.
Frontiers in Physiology
Signal transducer and activator of transcription-3 (STAT3) regulates inflammation, apoptosis, and protease expression, which are critical processes associated with airway injury and lung tissue destruction. However, the precise role of STAT3 in the development of airway diseases such as chronic obstructive pulmonary disease (COPD) has not been established. This study shows that cigarette smoke activates STAT3 in the lungs of mice. Since cigarette smoke activated STAT3 in the lung, we then evaluated how the loss of STAT3 would impact on smoke-mediated lung inflammation, protease expression, and apoptosis. STAT3+/+ and STAT3-/- mice were exposed to 8 days of cigarette smoke. Compared to the STAT3+/+ mice bronchoalveolar lavage fluid (BALF) cellularity was significantly elevated in the STAT3-/- mice both before and after cigarette smoke exposure, with the increase in cells primarily macrophages. In addition, smoke exposure induced significantly higher BALF protein levels of Interleukin-1a (IL-1α), and monocyte chemotactic protein-1 (MCP-1) and higher tissue expression of keratinocyte chemoattractant (KC) in the STAT3-/- mice. Lung mRNA expression of MMP-12 was increased in STAT3-/- at baseline. However, the smoke-induced increase in MMP-10 expression seen in the STAT3+/+ mice was not observed in the STAT3-/- mice. Moreover, lung protein levels of the anti-inflammatory proteins SOCS3 and IL-10 were markedly lower in the STAT3-/- mice compared to the STAT3+/+ mice. Lastly, apoptosis, as determined by caspase 3/7 activity assay, was increased in the STAT3-/- at baseline to levels comparable to those observed in the smoke-exposed STAT3+/+ mice. Together, these results indicate that the smoke-mediated induction of lung STAT3 activity may play a critical role in maintaining normal lung homeostasis and function. © 2013 Geraghty, Wyman, Garcia-Arcos, Dabo, Gadhvi and Foronjy. Source
Wallace A.M.,University of British Columbia |
Wallace A.M.,Columbia University |
Mercer B.A.,Columbia University |
He J.,University of British Columbia |
And 5 more authors.
Background: Prior studies have demonstrated that the distal 1.5 kb of the MMP-1 promoter is fundamental in directing the induction of the MMP-1 gene by cigarette smoke.Methods: To characterize the genetic variants in the MMP-1 cigarette smoke-responsive element, deep re-sequencing of this element was performed on DNA samples from participants in the Lung Health Study. Furthermore, evidence of Sp1 binding to the MMP-1 promoter was assessed using chromatin immunoprecipitation assays and the influence of cigarette smoke exposure on this interaction was evaluated in cultured human small airway epithelial cells.Results: Ten polymorphisms (four novel) were detected in the cigarette smoke-responsive element. Chromatin immunoprecipitation assays to assess the protein-DNA interactions at Sp1 sites in the MMP-1 promoter showed increased binding to the Sp1 sites in the cigarette smoke-responsive element in small airway epithelial cells treated with cigarette smoke extract. In contrast, a Sp1 site outside of the element exhibited the opposite effect. None of the polymorphisms were more prevalent in the fast decliners versus the slow decliners (fast decliners = mean -4.14% decline in FEV1% predicted per year vs. decline in FEV1% predicted per year).Conclusions: Sequencing analyses identified four novel polymorphisms within the cigarette smoke-responsive element of the MMP-1 promoter. This study identifies functional activity within the cigarette smoke-responsive element that is influenced by cigarette smoke and examines this region of the promoter within a small patient population. © 2012 Wallace et al.; licensee BioMed Central Ltd. Source