Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease

Mocchegiani, Eugenio; Giacconi, Robertina; Costarelli, Laura

doi:10.1097/01.mcp.0000410743.98087.12

Cited by 69 publications

(62 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pathogenesis of COPD is associated with an imbalance of metalloproteases (matrix metalloproteases [MMP] and a disintegrin and metalloprotease) and antimetalloproteases (tissue inhibitor of metalloproteases and a-2M) (25). In the present study, a notable up-regulation of metalloprotease family genes was evident, including Adamts9 and Mmp3 in the SS and AHR groups (a 2-4 times increase).…”

Section: Discussionsupporting

confidence: 54%

In Utero Exposure to Second-Hand Smoke Aggravates Adult Responses to Irritants

Xiao

Perveen²,

Paulsen³

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

In utero exposure to second-hand smoke (SHS) is associated with exacerbated asthmatic responses in children. We tested the hypothesis that in utero SHS will aggravate the lung responses of young adult mice re-exposed to SHS. We exposed Balb/c mice in utero to SHS (S) or filtered air (AIR; A), and re-exposed the male offspring daily from 11-15 weeks of age to either SHS (AS and SS) or AIR (AA and SA). After the adult exposures, we analyzed samples of bronchoalveolar lavage fluid (BALF), examined the results of histopathology, and assessed pulmonary function and gene expression changes in lung samples. In SS mice, compared with the other three groups (AA, AS, and SA), we found decreases in breathing frequency and increases in airway hyperresponsiveness (AHR), as well as low but significantly elevated concentrations of BALF proinflammatory cytokines (IL-1b, IL-6, and keratinocytederived chemokine). Lung morphometric analyses revealed enlarged airspaces and arteries in SA and SS mice compared with their in utero AIR counterparts, as well as increased collagen deposition in AS and SS mice. Unique gene expression profiles were found for in utero, adult, and combined exposures, as well as for mice with elevated AHR responses. The profibrotic metalloprotease genes, Adamts9 and Mmp3, were up-regulated in the SS and AHR groups, suggesting a role for in utero SHS exposure on the adult development of chronic obstructive pulmonary disease. Our results indicate that in utero exposures to environmentally relevant concentrations of SHS alter lung structure more severely than do adult SHS exposures of longer duration. These in utero exposures also aggravate AHR and promote a profibrotic milieu in adult lungs.Keywords: second-hand smoke; in utero exposure; airway hyperresponsiveness; lung structure changes; gene expressionIn utero exposure to second-hand smoke (SHS), which exerts striking effects on lung function (1), has been associated with exacerbated asthmatic responses in children (1, 2). Altered lung function, an increased risk of asthma, and persistent lung function deficits in children have been linked with in utero and postnatal exposures to SHS (3-7). The synergistic effects of in utero smoke exposure with various nontobacco allergens have also been reported. Mild in utero SHS exposure exacerbates responses of BALB/c mice exposed to ovalbumin (OVA) from 11-15 weeks of age (8). These functional, histological, and inflammatory responses are accompanied by distinct changes in lung gene expression (9). Children exposed in utero to maternal smoking manifest a higher risk of sensitization to house dust mites (10). A recent study of mice found that in utero smoke exposure promotes Th2 polarization and induces allergic asthma in response to Aspergillus fumigatus sensitization (11). Whether and how in utero SHS exposures potentiate subsequent adult physiological and transcriptome responses to SHS exposure, without any other irritant challenges, are not fully understood.Evidence also indicates that exposure to environmental pollu...

show abstract

Section: Discussionsupporting

confidence: 54%

In Utero Exposure to Second-Hand Smoke Aggravates Adult Responses to Irritants

Xiao

Perveen²,

Paulsen³

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…MMP1, MMP9 and MMP12 are produced by alveolar macrophages, and several studies in animals and humans have provided evidence that these MMPs are important in airway inflammation and the development of emphysema [6,7]. Cathepsin L (CTSL) and cathepsin S (CTSS) are lysosomal cysteine proteinases produced by alveolar macrophages [6] that may also be involved in COPD through degradation of elastin [8].…”

Section: Introductionmentioning

confidence: 99%

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

et al. 2013

View full text Add to dashboard Cite

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes.Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed.The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/ alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted.We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation. @ERSpublications MMP12 expression may play a role in the pathogenesis of emphysema and airflow limitation

show abstract

“…These studies have identified roles for matrix metalloproteinase (MMP) 1, MMP2, MMP9, and MMP12 and a disintegrin and metalloproteases 17 (ADAM17) and ADAM33 in the pathogenesis of COPD (reviewed in Ref. 24). With respect to MMP12, also known as macrophage elastase, mice deficient in this protease demonstrate resistance to cigarette smoke-induced emphysema (11), whereas transgenic overexpression of MMP12 in the lungs of mice accelerates emphysema and the development of bronchoalveolar adenocarcinoma (30).…”

mentioning

confidence: 99%

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

Nelson

Christmann

Dunaway

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Among several bacterial and viral pathogens, the atypical fungal organism Pneumocystis jirovecii has been implicated as a contributor to the pathogenesis of chronic obstructive pulmonary disease (COPD). In a previous study, we reported that Pneumocystis-colonized HIV-positive subjects had worse obstruction of airways and higher sputum levels of macrophage elastase/matrix metalloproteinase 12 (MMP12), a protease strongly associated with the development of COPD. Here, we examined parameters of Pneumocystis-induced MMP12 in the lungs of mice and its role in the lung immune response to murine Pneumocystis. Initial studies demonstrated that P. murina exposure induced Mmp12 mRNA expression in whole lungs and alveolar macrophages (AMs), which was dependent on the presence of CD4+ T cells as well as signal transducer and activator of transcription 6. Mmp12 mRNA expression was upregulated in AMs by interleukin (IL)-4 treatment, but downregulated by interferon (IFN)-γ, indicating preferential expression in alternatively activated (M2a) macrophages. IL-4 treatment induced the 54-kDa proenzyme form of MMP12 and the 22-kDa fully processed and active form, whereas IFN-γ failed to induce either. Despite a reported antimicrobial role in macrophage phagolysosomes, mice deficient in MMP12 were not found to be more susceptible to lung infection with P. murina. Collectively, our data indicate that MMP12 induction is a component of the P. murina-induced M2 response and thus provides insight into the link between Pneumocystis colonization/infection and exacerbations in COPD.

show abstract

Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease

Cited by 69 publications

References 82 publications

In Utero Exposure to Second-Hand Smoke Aggravates Adult Responses to Irritants

In Utero Exposure to Second-Hand Smoke Aggravates Adult Responses to Irritants

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

ExperimentalPneumocystislung infection promotes M2a alveolar macrophage-derived MMP12 production

Contact Info

Product

Resources

About