Animal models of emphysema.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease of human beings characterized by not fully reversible airflow limitation. Emphysema is the main pathological feature of COPD which causes high mortality worldwide every year and consumes a large amount of medical expenses. This paper was to review the establishment and evaluation methods of animal models of emphysema or COPD, and put forward some new ideas on animal selection, method of modeling, and model evaluation. DATA SOURCES: The author retrieved information from the PubMed database up to July 2019, using various combinations of search terms, including emphysema, model, and animal. STUDY SELECTION: Original articles, reviews, and other articles were searched and reviewed for animal models of emphysema. RESULTS: This review summarized animal models of emphysema from the perspectives of animal selection, emphysema mechanism, modeling method and model evaluation, and found that passive smoking is the classic method for developing animal model of emphysema, mice are more suitable for experimental study on emphysema. Compared with pulmonary function indicators, airway inflammation indicators and oxidative stress indicators, pathomorphological indicators of lung tissue are the most important parameters for evaluating the establishment of the animal model of emphysema. CONCLUSIONS: Mice model induced by passive smoking is the classic animal model of emphysema. Pathomorphological indicators are the most important parameters for evaluating the establishment of the animal model of emphysema.

Above the fray: Surface remodeling by secreted lysosomal enzymes leads to endocytosis-mediated plasma membrane repair.

The study of plasma membrane repair is coming of age. Mirroring human adolescence, the field shows at the same time signs of maturity and significant uncertainty, confusion and skepticism. Here we discuss concepts that emerged from experimental data over the years, some of which are solidly established while others are still subject to different interpretations. The firmly established concepts include the critical requirement for Ca(2+) in wound repair, and the role of rapid exocytosis of intracellular vesicles. Lysosomes are being increasingly recognized as the major vesicles involved in injury-induced exocytosis in many cell types, as a growing number of laboratories detect markers for these organelles on the cell surface and lysosomal hydrolases in the supernatant of wounded cells. The more recent observation of massive endocytosis following Ca(2+)-triggered exocytosis initially came as a surprise, but this finding is also being increasingly reported by different groups, shifting the discussion to the mechanisms by which endocytosis promotes repair, and whether it operates or not in parallel with the shedding of membrane blebs. We discuss how the abundant intracellular vesicles that undergo homotypic fusion close to wound sites, previously interpreted as exocytic membrane patches, actually acquire extracellular tracers demonstrating their endocytic origin. We also suggest that an initial, temporary patch that prevents cytosol loss until the bilayer is restored might result not from vesicular fusion, but from rapid Ca(2+)-dependent crosslinking and aggregation of cytosolic proteins. Finally, we propose that cell surface remodeling, orchestrated by the extracellular release of lysosomal hydrolases and perhaps also cytosolic molecules, may represent a key aspect of the plasma membrane repair mechanism that has received little attention so far.

Localization and stretch-dependence of lung elastase activity in development and compensatory growth.

Synthesis and remodeling of the lung matrix is necessary for primary and compensatory lung growth. Because cyclic negative force is applied to developing lung tissue during the respiratory cycle, we hypothesized that stretch is a critical regulator of lung matrix remodeling. By using quantitative image analysis of whole-lung and whole-lobe elastin in situ zymography images, we demonstrated that elastase activity increased twofold during the alveolar stage of postnatal lung morphogenesis in the mouse. Remodeling was restricted to alveolar walls and ducts and was nearly absent in dense elastin band structures. In the mouse pneumonectomy model of compensatory lung growth, elastase activity increased threefold, peaking at 14 days postpneumonectomy and was higher in the accessory lobe compared with other lobes. Remodeling during normal development and during compensatory lung growth was different with increased major airway and pulmonary arterial remodeling during development but not regeneration, and with homogenous remodeling throughout the parenchyma during development, but increased remodeling only in subpleural regions during compensatory lung growth. Left lung wax plombage prevented increased lung elastin during compensatory lung growth. To test whether the adult lung retains an innate capacity to remodel elastin, we developed a confocal microscope-compatible stretching device. In ex vivo adult mouse lung sections, lung elastase activity increased exponentially with strain and in peripheral regions of lung more than in central regions. Our study demonstrates that lung elastase activity is stretch-dependent and supports a model in which externally applied forces influence the composition, structure, and function of the matrix during periods of alveolar septation.

[Pseudomonas aeruginosa elastase inhibits immune phagocytosis mediated by pulmonary surfactant protein A].

OBJECTIVE: To investigate the relationship between Pseudomonas aeruginosa (P.aeruginosa) elastase and pulmonary surfactant protein A (SP-A) in host infected by P.aeruginosa. METHODS: C3H mice were intranasally infected with P.aeruginosa wild-type PAO1, ΔlasB mutant and genetic complement strain PDO240LasB to determine the difference of virulence between wide type and mutant. The ability to degrade SP-A in vitro by PAO1, ΔlasB and PDO240LasB was observed through co-incubation of equal bacteria and SP-A and detected by Western blotting. The susceptibility of bacteria to phagocytosis was assayed by in vitro experiment that bacteria treated with SP-A was incubated with mouse Raw264.7 macrophages. RESULTS: Compared with wide-type PAO1, the virulence of ΔlasB mutant was attenuated in the mouse model of P.aeruginosa infection because of the knock down of elastase expression. The ΔlasB mutant lost the ability to degrade SP-A when incubated with SP-A in vitro. The in vitro phagocytosis experiments showed that SP-A augmented the phagocytosis of ΔlasB mutant bacteria more efficiently than the wild-type PAO1. CONCLUSION: P.aeruginosa elastase provides a protection from phagocytic cells by degrading SP-A.

[The role of endogenous vascular elastase in coronary artery reconstruction in Kawasaki disease].

OBJECTIVE: To investigate the role of endogenous vascular elastase (EVE) in coronary artery between reconstruction among pediatric patients with Kawasaki disease (KD). METHODS: Sixty children who were diagnosed with KD between January 2012 and April 2013 were selected as the case group, and peripheral venous blood samples were collected on days 0-11 (pathological stage I) and days 12-25 (pathological stage II) after the onset of disease; another 60 children without KD who visited the hospital due to acute fever during the same period were selected as the control group, and fasting peripheral venous blood samples were collected in the acute stage of fever. For both groups, serum levels of EVE and interleukin-6 (IL-6) and plasma vascular endothelial growth factor (VEGF) level were measured by enzyme-linked immunosorbent assay. For the case group, ultrasonic cardiography was used to detect coronary artery lesions (CALs) at the first, second and fourth weekends. The correlations of EVE level with IL-6 and VEGF levels were evaluated by Pearson correlation analysis. RESULTS: Serum levels of EVE and IL-6 in the case group in pathological stages I and II were significantly higher than in the control group (P<0.05), but plasma VEGF levels in stages I and II were significantly lower than in the control group (P<0.05); in the case group, EVE and IL-6 levels were significantly higher in stage II than in stage I (P<0.05). In pathological stage II, KD patients with CALs had significantly higher serum levels of EVE and IL-6 but significantly lower plasma VEGF levels compared with those without CALs (P<0.05); KD patients with coronary artery aneurysms (CAAs) had significantly higher serum levels of EVE and IL-6 but significantly lower plasma VEGF level compared with those without CAAs (P<0.05 for all). EVE level was positively correlated with IL-6 level (r=0.915, P<0.05), yet negatively correlated with VEGF level (r=-0.769, P<0.05). CONCLUSIONS: EVE may participate in coronary artery reconstruction in children with KD. To interfere EVE activity may reduce and prevent CALs.

Pseudomonas aeruginosa elastase causes transient disruption of tight junctions and downregulation of PAR-2 in human nasal epithelial cells.

BACKGROUND: Pseudomonas aeruginosa causes chronic respiratory disease, and the elastase enzyme that it produces increases the permeability of airway epithelial cells owing to the disruption of tight junctions. P. aeruginosa is also implicated in prolonged chronic rhinosinusitis. However, the effects of P. aeruginosa elastase (PE) against the barrier formed by human nasal epithelial cells (HNECs) remain unknown. METHODS: To investigate the mechanisms involved in the disruption of tight junctions by PE in HNECs, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were used. The hTERT-HNECs were pretreated with inhibitors of various signal transduction pathways, PKC, MAPK, p38MAPK, PI3K, JNK, NF-κB, EGF receptor, proteasome, COX1 and COX2 before treatment with PE. Some cells were pretreated with siRNA and agonist of protease activated receptor-2 (PAR-2) before treatment with PE. Expression and structures of tight junctions were determined by Western blotting, real-time PCR, immunostaining and freeze-fracture. Transepithelial electrical resistance (TER) was examined as the epithelial barrier function. RESULTS: PE treatment transiently disrupted the epithelial barrier and downregulated the transmembrane proteins claudin-1 and -4, occludin, and tricellulin, but not the scaffold PDZ-expression proteins ZO-1 and -2 and adherens junction proteins E-cadherin and ß-catenin. The transient downregulation of tight junction proteins was controlled via distinct signal transduction pathways such as the PKC, MAPK, PI3K, p38 MAPK, JNK, COX-1 and -2, and NF-κB pathways. Furthermore, treatment with PE transiently decreased PAR-2 expression, which also regulated the expression of the tight junction proteins. Treatment with a PAR-2 agonist prevented the downregulation of the tight junction proteins after PE treatment in HNECs. CONCLUSIONS: PE transiently disrupts tight junctions in HNECs and downregulates PAR-2. The transient disruption of tight junctions by PE might occur repeatedly during chronic rhinosinusitis.

Development of a formula for estimating plasma free cortisol concentration from a measured total cortisol concentration when elastase-cleaved and intact corticosteroid binding globulin coexist.

Cortisol bound to corticosteroid binding globulin (CBG) contributes up to 90% of the total cortisol concentration in circulation. Therefore, changes in the binding kinetics of cortisol to CBG can potentially impact on the concentration of free cortisol, the only form that is responsible for the physiological function of the hormone. When CBG is cleaved into elastase-cleaved CBG (eCBG) by the activity of neutrophil elastase, its affinity for cortisol is reduced. Therefore, when eCBG coexists with intact CBG (iCBG) in plasma, the calculation of free cortisol concentration based on the formulae that considers only one CBG pool with the same affinity for cortisol may be inappropriate. In this study, we developed in vivo and in vitro models of cortisol partitioning which considers two CBG pools, iCBG and eCBG, with different affinities for cortisol, and deduce a new formula for calculating plasma free cortisol concentration. The formula provides better estimates of free cortisol concentration than previously used formulae when measurements of the concentrations of the two CBG forms are available. The model can also be used to estimate the affinity of CBG and albumin for cortisol in different clinical groups. We found no significant difference in the estimated affinity of CBG and albumin for cortisol in normal, sepsis and septic shock groups, although free cortisol was higher in sepsis and septic shock groups. The in vivo model also demonstrated that the concentration of interstitial free cortisol is increased locally at a site of inflammation where iCBG is cleaved to form eCBG by the activity of elastase released by neutrophils. This supports the argument that the cleavage of iCBG at sites of inflammation leads to more lower-affinity eCBG and may be a mechanism that permits the local concentration of free cortisol to increase at these sites, while allowing basal free cortisol concentrations at other sites to remain unaffected.

Neutrophil serine proteases mediate inflammatory cell recruitment by glomerular endothelium and progression towards dysfunction.

BACKGROUND: Neutrophil recruitment into glomerular tissues and reduced capillary wall integrity has been implicated in the development of vasculitic glomerulonephritis (VGN). This study investigated the stages and mechanisms through which neutrophil serine proteases (SPs), proteinase 3 (PR3) or elastase contribute to endothelial dysfunction. METHODS: Protease-induced damage to endothelium and adhesion molecule upregulation was measured by viability assays and ELISA. Neutrophil/platelet adhesion to human glomerular and umbilical vein endothelium was assessed using in vitro adhesion assays. RESULTS: PR3 and elastase (1 µg/mL, 2 h) significantly induced neutrophil adhesion to endothelial cells (EnC) whilst PR3 also enhanced platelet-EnC interactions. This neutrophil adhesion was associated with enhanced P-selectin expression and required CXCL8 receptor involvement, and could be inhibited by blocking the P-selectin ligand PSGL-1. SPs induced damage in a time- and dose-dependent fashion, decreasing cell monolayer integrity followed by cell membrane integrity, inducing caspase-3 activation and p21 cleavage. However, SPs caused significant EnC damage with increasing concentrations and prolonged exposures. CONCLUSION: Neutrophil SPs induce a pro-adhesive phenotype in glomerular endothelium primarily by inducing neutrophil and platelet adhesion that transits to dysfunction after high/prolonged exposures. Dysregulated release of these enzymes within glomeruli may contribute to injury during diseases such as VGN.

Importance of elastase production in development of invasive aspergillosis.

OBJECTIVE: To evaluate the relationship between elastase activity of different Aspergillus fumigatus (A. fumigatus) isolates and their pathogenicity in mice. MATERIAL AND METHODS: The animals were intravenously (IV) infected with 1×10(6) conidia/mouse. The elastase activity in mice sera and survival time were determined. All animals were sacrified at the end of the fourth week, and autopsies were performed for histopathological examination. The tissue sections were stained with Periodic Acid Schiff (PAS) and Verhoeff's techniques. RESULTS: The highest elastase activity was associated with the sera of infected mice with elastase-producing A. fumigatus AIR78 as standard strain (0.18±0.02mm), followed by infected animals with elastase-producing isolates (0.16±0.02mm) and control mice (0.14±0.02mm). The elastase activity index (EAI) was determined in value of 0.92±0.27. The survival times in mice infected with elastase-producing isolate and in control group were 21.6 and 30 days, respectively. Histopathological studies showed that the heart and kidneys were more infected by Aspergillus hyphae than other tissues. CONCLUSION: It was concluded that there is a significant relationship between elastase activity and survival time in mice with aspergillosis.

[Protease-dependent cell entry mechanism of coronaviruses].

Previous studies have demonstrated that the SARS-CoV S protein requires proteolytic cleavage by elastase, cathepsin or TMPRSS2 for S-mediated cell-cell or virus-cell membrane fusion. Activation of viral glycoprotein (GP) by protease also has been reported for influenza virus. The most distinctive difference between influenza virus and SARS-CoV is the stage during virus replication in which viral glycoproteins are cleaved by proteases. In influenza virus, the protease makes a simple cut in the GP during maturation. In contrast, SARS-CoV S protein is cleaved by the protease following receptor-induced conformational changes. The protease cleavage site in S protein is thought to be exposed only after receptor binding. In support of this model, we reported that the S protein of mouse hepatitis virus type 2 (MHV-2), which is highly similar to the S protein of SARS-CoV, requires two-step conformational changes mediated by sequential receptor binding and proteolysis to be activated for membrane fusion. Such a mechanism allows for tight temporal control over fusion by protecting the activating cleavage site from premature proteolysis yet allowing efficient cleavage upon binding to the receptor on target cells.

Complex receptor-ligand dynamics control the response of the VEGF system to protease injury.

BACKGROUND: Vascular homeostasis and response to injury are dependent on the coordinated activity of growth factors such as vascular endothelial growth factor-A (VEGF). VEGF signaling is mediated by VEGF receptors 1 (VEGFR1) and 2 (VEGFR2). VEGF also binds to extracellular matrix (ECM) and neuropilin (NP), a cell surface glycoprotein that enhances VEGF binding to VEGFR2 while inhibiting VEGF-VEGFR1 interactions. Proteases such as neutrophil elastase release VEGF bound to ECM; however, this results in proteolytic processing of VEGF to a smaller species termed VEGF fragment (VEGFf). We hypothesized that the generation and presence of VEGFf would have significant effects on the binding distribution of VEGF. RESULTS: We show that VEGFf, unlike VEGF, does not bind ECM, fibronectin, or NP-1. Using computational simulations, we find that excess VEGFf can lead to increased binding of VEGF to VEGFR2 through VEGFf binding to VEGFR1 and subsequent liberation of NP-1. We show experimentally that VEGF-induced migration has a biphasic response to conversion of VEGF to VEGFf. Simulations suggest that a simple change in VEGFR1 or VEGFR2 complexes are unlikely to be responsible and that a more complex integration of signals is more likely involved. CONCLUSIONS: These findings suggest that proteolytic damage at sites of tissue injury and inflammation has the potential to modulate the VEGF system through a complex process and highlight the need for quantitative analysis to reveal mechanisms of growth factor control.

A high omega-3 fatty acid diet mitigates murine pancreatic precancer development.

BACKGROUND: Diets containing omega-3 (ω-3) fat have been associated with decreased tumor development in the colon, breast, and prostate. We assessed the effects of a diet rich in ω-3 fat on the development of pancreatic precancer in elastase (EL)-Kras transgenic mice and examined the effect of an ω-3 fatty acid on pancreatic cancer cells in vitro. MATERIALS AND METHODS: Two cohorts of EL-Kras mice were fed a high ω-3 fat diet (23% menhaden oil) for 8 and 11 mo and compared with age-matched EL-Kras mice fed standard chow (5% fat). Pancreata from all mice were scored for incidence and frequency of precancerous lesions. Immunohistochemistry was performed for proliferating cell nuclear antigen (PCNA) to assess proliferative index in lesions of mice fed either a high ω-3 or standard diet. In vitro, the effect of the ω-3 fatty acid, docosahexaenoic acid (DHA), on two pancreatic cancer cell lines was assessed. Cancer cell proliferation was assessed with an MTT assay; cell cycle analysis was performed by flow cytometry; and apoptosis was assessed with annexin/PI staining. RESULTS: The incidence, frequency, and proliferative index of pancreatic precancer in EL-Kras mice was reduced in mice fed a high ω-3 fat diet compared with mice fed a standard chow. In vitro, DHA treatment resulted in a concentration-dependent decrease in proliferation through both G1/G0 cell cycle arrest and induction of apoptosis. CONCLUSIONS: A high ω-3 fat diet mitigates pancreatic precancer by inhibition of cellular proliferation through induction of cell cycle arrest and apoptosis.

Role of elastases in the pathogenesis of chronic obstructive pulmonary disease: implications for treatment.

Neutrophil elastase, metalloproteinases, and their inhibitors play an important role in the development of chronic obstructive pulmonary disease (COPD), resulting in extensive tissue damage and malfunctioning of the airways. Nearly fifty years after the protease-antiprotease imbalance hypothesis has been suggested for the cause of emphysema, it is still appealing, but it does not explain the considerable variation in the clinical expressions of emphysema. However, there are many recent research findings to support the imbalance hypothesis as will be shown in this review. Although limited, there might be openings for the treatment of the disease.

Physiology of skin aging.

Skin is the most voluminous organ of the body. It assumes several important physiological functions and represents also a "social interface" between an individual and other members of society. This is the main reason its age-dependent modifications are in the forefront of dermatological research and of the "anti-aging" cosmetic industry. Here we concentrate on some aspects only of skin aging, as far as the cellular and extracellular matrix components of skin are concerned. Most well studied mechanisms of skin aging can be situated at the postgenetic level, both epigenetic and post-translational mechanisms being involved. Some of these mechanisms will be reviewed as well as the capacity of fucose- and rhamnose-rich oligo- and polysaccharides (FROP and RROP) to counteract several of the mechanisms involved in skin aging.

Entry from the cell surface of severe acute respiratory syndrome coronavirus with cleaved S protein as revealed by pseudotype virus bearing cleaved S protein.

Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is known to take an endosomal pathway for cell entry; however, it is thought to enter directly from the cell surface when a receptor-bound virion spike (S) protein is affected by trypsin, which induces cleavage of the S protein and activates its fusion potential. This suggests that SARS-CoV bearing a cleaved form of the S protein can enter cells directly from the cell surface without trypsin treatment. To explore this possibility, we introduced a furin-like cleavage sequence in the S protein at amino acids 798 to 801 and found that the mutated S protein was cleaved and induced cell fusion without trypsin treatment when expressed on the cell surface. Furthermore, a pseudotype virus bearing a cleaved S protein was revealed to infect cells in the presence of a lysosomotropic agent as well as a protease inhibitor, both of which are known to block SARS-CoV infection via an endosome, whereas the infection of pseudotypes with an uncleaved, wild-type S protein was blocked by these agents. A heptad repeat peptide, derived from a SARS-CoV S protein that is known to efficiently block infections from the cell surface, blocked the infection by a pseudotype with a cleaved S protein but not that with an uncleaved S protein. Those results indicate that SARS-CoV with a cleaved S protein is able to enter cells directly from the cell surface and agree with the previous observation of the protease-mediated cell surface entry of SARS-CoV.

Recent advances in characterizing biological mechanisms underlying UV-induced wrinkles: a pivotal role of fibrobrast-derived elastase.

In clinical studies, the formation of facial wrinkles has been closely linked to the loss of elastic properties of the skin. Cumulative irradiation with ultraviolet (UV) B at suberythemal doses significantly reduces the elastic properties of the skin, resulting in the formation of wrinkles. In in vitro studies, we identified a paracrine pathway between keratinocytes and fibroblasts, which leads to wrinkle formation via the up-regulation of fibroblast elastases that degrade elastic fibers. UVB irradiation stimulates the activity of fibroblast elastases in animal skin. Scanning electron microscopy revealed that cumulative UVB irradiation elicits a marked alteration in the three-dimensional structure of elastic fibers, which is closely associated with the subsequent reduction in the elastic properties of the skin, resulting in wrinkle formation. Studies using anti-wrinkle treatments suggest a close relationship between the recovery of wrinkles and an improvement in the linearity of elastic fibers. Those studies also suggest a close correlation between the recovery in the linearity of elastic fibers and the improvement in skin elasticity. In a study using ovariectomized animals, we characterized the important role of elastase in their high vulnerability to UV-induced wrinkle formation. A synthetic inhibitor specific for fibroblast elastases significantly prevents wrinkle formation without reducing the elastic properties of the skin, accompanied by minor damage in elastic fibers. Finally, we identified an effective extract of Zingiber officinale (L.) Rose from a screen of many herb extracts, which has a safe and potent inhibitory activity against fibroblast elastases. Animal studies using the L. Rose extract revealed that it has significant preventive effects against UVB-induced wrinkle formation, which occur in concert with beneficial effects on skin elasticity. A 1-year clinical study on human facial skin to determine the efficacy of the L. Rose extract demonstrated that it inhibits the UV-induced decrease in skin elasticity and prevents or improves wrinkle formation in skin around the corner of the eye without changing the water content of the stratum corneum. Our long-term studies support our hypothesis for a mechanism of wrinkle formation in which cytokine expression is activated by UV irradiation and triggers dermal fibroblasts to increase the expression of elastase. That increase in elastase results in the deterioration of the three-dimensional architecture of elastic fibers, reducing skin elasticity and finally leading to the formation of wrinkles.

Identification of glucocorticoid-regulated genes that control cell proliferation during murine respiratory development.

Glucocorticoids play a vital role in fetal respiratory development and act via the intracellular glucocorticoid receptor (GR) to regulate transcription of key target genes. GR-null mice die at birth due to respiratory dysfunction associated with hypercellularity and atelectasis. To identify events associated with this lung phenotype we examined perinatal cellular proliferation rates and apoptotic indices. We demonstrate that compared to wild-type controls, day 18.5 postcoitum (p.c.) GR-null mouse lungs display significantly increased cell proliferation rates (1.8-fold P < 0.05) and no change in apoptosis. To examine underlying molecular mechanisms, we compared whole genome expression profiles by microarray analysis at 18.5 days p.c. Pathways relating to cell proliferation, division and cell cycle were significantly down-regulated while pathways relating to carbohydrate metabolism, kinase activities and immune responses were significantly up-regulated. Differential levels of gene expression were verified by quantitative-RT-PCR and/or Northern analysis. Key regulators of proliferation differentially expressed in the lung of 18.5 p.c. GR-null lungs included p21 CIP1 (decreased 2.9-fold, P < 0.05), a negative regulator of the cell cycle, and Mdk (increased 6.0-fold, P < 0.05), a lung growth factor. The more under-expressed genes in 18.5 p.c. GR-null lungs included Chi3l3 (11-fold, P < 0.05), a macrophage inflammatory response gene and Ela1 (9.4-fold, P < 0.05), an extracellular matrix remodeling enzyme. Our results demonstrate that GR affects the transcriptional status of a number of regulatory processes during late fetal lung development. Amongst these processes is cell proliferation whereby GR induces expression of cell cycle repressors while suppressing induction of a well characterized cell cycle stimulator.

Human pancreatic digestive enzymes.

A primary function of the pancreas is to produce digestive enzymes that are delivered to the small intestine for the hydrolysis of complex nutrients. Much of our understanding of digestive enzymes comes from studies in animals. New technologies and the availability of the sequence of the human genome allow for a critical review of older reports and assumptions based on animal studies. This report updates our understanding of human pancreatic digestive enzymes with a focus on new insights into the biology of human proteases, lipases and amylases.

The pathogenesis of COPD: lessons learned from in vivo animal models.

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitations, that are not fully reversible. COPD is a major cause of chronic morbidity and mortality throughout the world. Tobacco smoking is a most important risk factor for the development of COPD. However, only 10 to 20% smokers develop clinically significant COPD. The detailed pathogenesis also remains to be elucidated. In vivo animal models provided some clues to help clarify the pathogenesis. Several important factors such as matrix metalloproteinases, apoptosis, protease-antiprotease imbalance, are considered to contribute to the development of COPD. In addition to these factors, chronic inflammation affects lung morphogenesis and causes several pathological involvements including COPD. In this article, we review the pathogenesis of COPD, while especially focusing on the recent advances and the effects of chronic inflammation using an in vivo animal model. This article aims at offering valuable information for both proceeding with COPD research as well as for developing a new medicines for the treatment of COPD.