Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

The interstitial collagenase matrix metalloprotein-ase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15–20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERK-dependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema. The interstitial collagenase matrix metalloprotein-ase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15–20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERK-dependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema. Cigarette smoke exposure is the primary cause of chronic obstructive pulmonary disease, which includes emphysema and chronic bronchitis (1Croxton T.L. Weinmann G.G. Senior R.M. Wise R. Crapo J.D. Buist S. Am. J. Respir. Crit. Care. Med. 2003; 167: 1142-1149Crossref PubMed Scopus (114) Google Scholar). Cigarette smoking stimulates recruitment of inflammatory cells, cell death, and protease production (2Carp H. Janoff A. Am. Rev. Respir. Dis. 1978; 118: 617-621PubMed Google Scholar, 3Hautamaki R. Kobayashi D. Senior R. Shapiro S. Science. 1997; 277: 2002-2004Crossref PubMed Scopus (1250) Google Scholar, 4Kuschner W. D'Alessandro A. Wong H. Blanc P. Eur. Respir. J. 1996; 9: 1989-1994Crossref PubMed Scopus (303) Google Scholar, 5Sopori M. Nat. Rev. Immunol. 2002; 2: 372-377Crossref PubMed Scopus (914) Google Scholar, 6Wright J. Churg A. Am. Rev. Respir. Dis. 1990; 142: 1422-1428Crossref PubMed Scopus (152) Google Scholar). Chronic obstructive pulmonary disease pathology includes small airway inflammation, destruction of airway parenchyma (7Jeffrey P. Am. J. Respir. Crit. Care Med. 2001; 164: S28-S38Crossref PubMed Scopus (779) Google Scholar), and elevated protease expression (8Segura-Valdez L. Pardo A. Gaxiola M. Uhal B. Becerril C. Selman M. Chest. 2000; 117: 684-694Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar, 9Imai K. Dalal S. Chen E. Downey R. Schulman L. Ginsburg M. D'Armiento J. Am. J. Respir. Crit. Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar). However, the intracellular signaling mechanisms activated by tobacco smoke that mediate the protease/antiprotease imbalance and subsequent matrix degradation in the lungs are not well understood. Increased protease levels are present in lung tissue and lavage fluid from animal models and patients with emphysema (3Hautamaki R. Kobayashi D. Senior R. Shapiro S. Science. 1997; 277: 2002-2004Crossref PubMed Scopus (1250) Google Scholar, 7Jeffrey P. Am. J. Respir. Crit. Care Med. 2001; 164: S28-S38Crossref PubMed Scopus (779) Google Scholar, 8Segura-Valdez L. Pardo A. Gaxiola M. Uhal B. Becerril C. Selman M. Chest. 2000; 117: 684-694Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar, 10D'Armiento J. Dalal S. Okada Y. Berg R. Chada K. Cell. 1992; 71: 955-961Abstract Full Text PDF PubMed Scopus (328) Google Scholar, 11Fletcher C. Peto R. Tinker C. Speizer F. The Natural History of Chronic Bronchitis and Emphysema. Oxford University Press, Oxford, UK1976: 82-85Google Scholar, 12Wright J. Churg A. Am. J. Physiol. 1995; 268: L17-L20PubMed Google Scholar). In patients with deficiency of the elastase inhibitor α1-antitrypsin, the decreased inhibitor concentration leads to increased elastolytic activity and risk for development of emphysema. Studies in mice reveal that knocking out metalloelastase (MMP-12) 1The abbreviations used are: MMP, matrix metalloproteinase; IL, interleukin; CSE, cigarette smoke extract; SAEC, small airway epithelial cell; ERK, extracellular signal-regulated kinase; p-ERK, phospho-ERK. confers resistance to cigarette smoke-induced emphysema (3Hautamaki R. Kobayashi D. Senior R. Shapiro S. Science. 1997; 277: 2002-2004Crossref PubMed Scopus (1250) Google Scholar), although levels of the enzyme are not elevated in human disease (9Imai K. Dalal S. Chen E. Downey R. Schulman L. Ginsburg M. D'Armiento J. Am. J. Respir. Crit. Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar). Evidence from human tissue and animal models support a role for collagenolytic enzymes in emphysema pathogenesis (9Imai K. Dalal S. Chen E. Downey R. Schulman L. Ginsburg M. D'Armiento J. Am. J. Respir. Crit. Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar, 10D'Armiento J. Dalal S. Okada Y. Berg R. Chada K. Cell. 1992; 71: 955-961Abstract Full Text PDF PubMed Scopus (328) Google Scholar, 13Shiomi T. Okada Y. Foronjy B. Schiltz J. Jaenish R. D'Armiento J. Exp. Lung Res. 2003; 29: 1-15Crossref PubMed Scopus (39) Google Scholar). Elevated MMP-1 levels and decreased pulmonary collagen content are measured in guinea pigs after cigarette smoke exposure (12Wright J. Churg A. Am. J. Physiol. 1995; 268: L17-L20PubMed Google Scholar, 14Selman M. Montano M. Ramos C. Vanda B. Becerril C. Delgado J. Sansores R. Barrios R. Pardo A. Am. J. Physiol. 1996; 271: L734-L743PubMed Google Scholar). Transgenic mice expressing human collagenase (MMP-1) develop emphysematous changes in their lungs (10D'Armiento J. Dalal S. Okada Y. Berg R. Chada K. Cell. 1992; 71: 955-961Abstract Full Text PDF PubMed Scopus (328) Google Scholar) caused by months of proteolytic damage to the lung parenchyma (15Foronjy R. Okada Y. Cole R. D'Armiento J. Am. J. Physiol. 2003; 284: L727-L737Crossref PubMed Scopus (82) Google Scholar). Human studies reveal increased collagenolytic activity in bronchoalveolar lavage fluid and lung tissue from patients with chronic obstructive pulmonary disease (8Segura-Valdez L. Pardo A. Gaxiola M. Uhal B. Becerril C. Selman M. Chest. 2000; 117: 684-694Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar, 16Finlay G.A. O'Driscoll L. Russell K.J. D'Arcy E.M. Masterson J.B. Fitzgerald M.X. O'Connor C. Am. J. Respir. Crit. Care Med. 1997; 156: 240-247Crossref PubMed Scopus (390) Google Scholar, 17Ohnishi K. Takagi M. Kurokawa Y. Satomi S. Konttinen Y. Lab. Investig. 1998; 78: 1077-1087PubMed Google Scholar). In addition, a recent report identified MMP-1 mRNA and protein in lung samples from human emphysema patients but not in lung samples from healthy subjects (9Imai K. Dalal S. Chen E. Downey R. Schulman L. Ginsburg M. D'Armiento J. Am. J. Respir. Crit. Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar). Interestingly, in the human studies, MMP-1 was detected in pneumocytes from patients with emphysema and not from smokers without disease (9Imai K. Dalal S. Chen E. Downey R. Schulman L. Ginsburg M. D'Armiento J. Am. J. Respir. Crit. Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar). Together, the above studies suggest that MMP-1 is active in the airways and lung tissue of persons with emphysema and that continued MMP-1 expression contributes to tissue breakdown. The current study was performed to elucidate signaling pathways activated by cigarette smoke that mediate the MMP-1 expression associated with emphysema. Cell Culture and Human Lung Tissue—Human small airway epithelial cells (SAECs) were cultured according to supplier instructions (Clonetics, San Diego, California). Human lung tissue was obtained at Columbia Presbyterian Medical Center (New York, NY) (Institutional Review Board protocol no. 9956). These samples were used in a previous study by our laboratory (9Imai K. Dalal S. Chen E. Downey R. Schulman L. Ginsburg M. D'Armiento J. Am. J. Respir. Crit. Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar). Emphysematous lung tissues (n = 6) were from recipient lungs obtained at transplant or lung volume reduction procedures. Patients had stopped smoking for at least three months. Normal tissues (n = 7) were from accidental death victims or donor lungs harvested for transplant but not used because of recipient complications. All samples were examined for the presence of emphysema, fibrosis, and infection. All emphysema lungs were from persons with a history of smoking. Normal sample N1 was from an active smoker. Assays were performed by operators blinded to the disease status of the samples, which was revealed by the principle investigator only after the experimental data had been collected. Reagents—Unless specified, all reagents were from Calbiochem. Stock solutions of IL-1α and IL-1β were diluted in small airway growth medium to 10 ng/ml. Kinase inhibitors were diluted in small airway growth medium (0.1 μm calphostin C, 1 μm herbimycin A, 40 μm PD98059, 20 μm SB230580, and 20 μm UO126) and added to cells 1 h before treatment with interleukins and CSE. Preparation of Cigarette Smoke Extract—Cigarette smoke extract (CSE) was prepared using a modified protocol (18Laurent P. Janoff A. Kagan H. Am. Rev. Respir. Dis. 1983; 127: 189-192PubMed Google Scholar). Briefly, a Barnant vacuum pump operating at constant airflow was used to draw the smoke of one unfiltered 2R1 reference cigarette (University of Kentucky) through 25 ml of Dulbecco's phosphate-buffered saline. This solution (100% CSE) was adjusted to pH 7.4, filtered, added to small airway growth medium to a final concentration of 2% or 5%, and added to cells immediately. Northern Blotting—Ten micrograms of total SAEC RNA were separated on a 1.2% agarose-formaldehyde gel and transferred to nylon (Hybond-N; Amersham Biosciences). Human MMP-1, MMP-13, TIMP-1, and glyceraldehyde-3-phosphate dehydrogenase cDNA probes were labeled with α-32PdCTP using Ready-to-Go DNA Labeling Beads (Amersham Biosciences). In some experiments, membranes were hybridized with a 28S oligonucleotide probe labeled with γ-32PATP to control for loading. Immunoblot Analyses—SAEC monolayers were scraped in cold phosphate-buffered saline and resuspended in 100 μl of protein lysis buffer (50 mm Tris, pH 8.0, 150 mm NaCl, 1% Triton X-100, 10 μg/ml leupeptin, 10 μg/ml aprotinin, 2 μg/ml pepstatin A, 1 mm Na3VO4, and 1 mm phenylmethylsulfonyl fluoride), centrifuged, and 20 μg of supernatant were separated on 12% SDS-polyacrylamide gels and transferred to membranes ERK and the Thr-202 and Tyr-204 of Cell were detected with reagents MMP-1 and expression was in SAEC using the Human MMP-1 (Amersham which and MMP-1 with in a of ng/ml. were in a at were to total protein and to using a of human MMP-1 activity SAEC was activated with and in the MMP-1 (Amersham which active MMP-1 in the of with a of ng/ml. In addition, was used in a which of labeled collagen P. M. E. L. W. H. K. J. 2002; PubMed Scopus Google Scholar). were using analysis of with using San Diego, All were performed using in was ERK were in mitogen activated protein kinase lysis buffer mm pH 7.4, 2 mm pH 8.0, 150 mm NaCl, 2 mm 10 μg/ml leupeptin, 10 μg/ml aprotinin, 1 mm Na3VO4, 1 mm phenylmethylsulfonyl Human lung was in mitogen activated protein kinase lysis buffer using a tissue at for 20 and ERK activity in was using the protein kinase enzyme (Amersham Biosciences). activity is in of transferred from to a kinase activity was measured in the of This a of to of All data are and are from at least three experiments. of protein from SAEC or (50 were separated by through a gel The gels were for 1 h with Triton X-100, by with buffer (50 mm pH mm 1 μm and 1% Triton were with and in and The presence of was by gels in buffer the inhibitor the in vivo of smoke mice were to cigarette smoke in a smoking were to 6 h of and smoke from for for various of in the not not mice were to were and were by an of The lung was in protein lysis buffer and 100 μg of protein was by The lung was at 25 with for 20 and in for h before were by the for Care and of Columbia of of lungs from control and mice were for ERK were and and was performed by for in 10 mm pH activity was with and were for 1 h in were with primary ERK and p-ERK, at by with a were for with and was performed San California). were with lung with of which not of Human lung tissues in were in a tissue and in and were of by were and protein was with in phosphate-buffered saline. primary was used at at by with a for 1 h at was detected with were with phosphate-buffered using and with a of were the using MMP-1 in studies by our laboratory (9Imai K. Dalal S. Chen E. Downey R. Schulman L. Ginsburg M. D'Armiento J. Am. J. Respir. Crit. Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar) and (8Segura-Valdez L. Pardo A. Gaxiola M. Uhal B. Becerril C. Selman M. Chest. 2000; 117: 684-694Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar) MMP-1 expression in lung epithelial cells of patients with emphysema. human were with to cigarette smoke directly MMP-1 expression in cells. were with IL-1α or because been to MMP-1 expression in and cells R. Press, San Google Scholar). Northern analysis revealed that exposure to induced a in MMP-1 Interestingly, treatment with in with IL-1α or IL-1β in MMP-1 expression treatment with treatment with had The inhibitor not with treatment the in MMP-1 protein in SAEC by MMP-1 protein expression which increased after exposure for 2% CSE, and for CSE, Treatment with the inflammatory IL-1α not MMP-1 protein in with IL-1α induced MMP-1 expression Treatment with IL-1β not MMP-1 expression to IL-1β significantly induced MMP-1 protein levels This was not that with = but of SAEC was for MMP-1 activity collagenase activity Treatment with 2% had but increased activity was with IL-1α not collagenase activity but IL-1α with significantly MMP-1 activity Treatment with IL-1β not collagenase activity but IL-1β in with significantly increased collagenase activity activity in SAEC using and which not after exposure to were in the ERK MMP-1 in define the intracellular signaling mechanisms airway MMP-1 induction by cigarette smoke and were with protein kinase inhibitors before exposure to or to ERK, and protein kinase pathways because of their in expression S. R. S. Respir. Res. 2002; PubMed Scopus Google Scholar, R. A. A. S. T. J. Investig. Med. 2002; PubMed Scopus Google Scholar, M. L. D. B. C. Crit. Rev. 1996; PubMed Scopus Google Scholar). Northern analysis showed that treatment with increased MMP-1 mRNA in for 1 h with 40 μm inhibitor of protein kinase the kinase of showed MMP-1 mRNA expression 1 and In addition, in MMP-1 2 and 6) and in MMP-1 and MMP-1 induction by and IL-1α in and The inhibitor herbimycin and protein kinase inhibitor calphostin (0.1 had on MMP-1 induction or IL-1α The inhibitors had on These data that and protein kinase are not in MMP-1 induction by cigarette smoke or IL-1α in human airway epithelial cells in is that data support a role for ERK in the SAEC response to cigarette To out the that the of MMP-1 was caused by of at the used S. H. M. P. J. 2000; PubMed Scopus Google Scholar), we performed response In addition, we our studies to which the of not MMP-1 induction by cigarette In of the of to MMP-1 mRNA 2 with The of was and calphostin not induction of MMP-1 by CSE. MMP-1 protein levels were examined after of ERK with reduction in MMP-1 protein was in from for 1 h with 40 μm Treatment for h with induced MMP-1 protein levels of This was by CSE, significantly MMP-1 protein levels measured in the from with in were the that of this that is a for ERK in MMP-1 induction by cigarette In addition, of with a ERK inhibitor 20 induction of MMP-1 activity by of = MMP-1 in analysis revealed that treatment with μm increased MMP-1 mRNA expression This induction not through or ERK because with 20 μm or 40 μm not MMP-1 not MMP-13, interstitial collagenase ERK by although and MMP-1 expression in ERK In data that the intracellular MMP-1 expression during exposure are to cigarette smoke and are not a to an increased not or and with or had on These studies that cultured human small airway epithelial cells to and by expression of MMP-1 but not ERK in examined the of to ERK increased activity activity at of of was a in activity for control and cells at with activity that was significantly control = and continued to during the treatment = In addition, increased expression of was detected by at after treatment and was present at Increased was in alveolar epithelial cells with not not phosphorylation of or activated protein kinase not study of the of smoke on ERK signaling revealed significantly increased ERK activity after treatment with CSE, compared with above = These that ERK is directly activated by in human airway cells in of ERK in Lung by Cigarette smoke exposure in vivo a of cell in the and because cell studies the of animal we performed in vivo studies to the signaling pathways activated in lung after exposure to cigarette of lung showed increased at 10 days of smoke exposure compared with lungs from control mice of lung tissue revealed in airway lining cells and cells in control with in alveolar cells and expression of is in airway lining cells, well in macrophages in the alveolar at 10 days of smoke exposure and airway and alveolar was present at 6 months of exposure and was detected in with of not These data that cigarette smoke in airway epithelial cells, alveolar cells, and alveolar macrophages in Emphysematous Human our in vitro and animal studies revealed directly increased activity with smoke we obtained human lung samples from patients with emphysema to changes in were associated with disease. previous study by our laboratory (9Imai K. 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Care Med. 2001; 163: 786-791Crossref PubMed Scopus (236) Google Scholar) showed that emphysematous lungs MMP-1 lungs To this MMP-1 expression with elevated protein we human samples for were performed in the of the (ERK) to protein phosphorylation in and emphysematous was detected However, activity was significantly levels were detected in lung from patients with emphysema, compared with healthy control subjects above = levels of ERK in human lung analysis revealed that emphysematous lungs levels lungs in were detected not These reveal a potential role for in emphysema Interestingly, expression in lung was emphysematous of smoking lung tissue from an active without emphysema showed levels of compared with patients with emphysema. that activity is to the presence of emphysema in human not a of smoking a of elevated in lung we performed on human lung to identify the of prepared lung tissue from a with emphysema and from a without emphysema. is in the sample However, increased is detected in the of cells lining the airways well in alveolar cells in the emphysema sample studies the cell The data in this study for of ERK and MMP-1 in the lungs of patients with emphysema. expression in the airways of tobacco smokers (3Hautamaki R. 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