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Animal Models
No full textThe main purpose of studying animal models of human disease is to gain insight into the underlying mechanisms of the disease. The recognition that chronic obstructive pulmonary disease (COPD) is a global health problem with no effective treatment has resulted in recent years in an explosion of new animal models of emphysema, a major component of COPD.
The present work is a review of some selected animal models developed in recent years that in the eyes of the authors, may provide new insight into the pathogenesis of emphysema and COPD
DOES NEUTROPHIL ELASTASE CONSTITUTE A PATHOGENIC LINK BETWEEN EMPHYSEMA AND FIBROSIS? EVIDENCE FROM ANIMAL MODELS
No full textecent data suggest that the separation of emphysema from fibrosis is not as it was thought in early studies. These two pathologies may be present at the same time in human lungs, in lungs of mice after cigarette-smoke or bleomycin (BLM) exposure, or in mouse lungs instilled with elastolytic enzymes. According to the current view, pulmonary emphysema originates from an imbalance between elastinolytic proteases and their inhibitors. Recently, a significant role for the antiproteases was also suggested in the modulation of fibrotic changes.
In this study we investigate whether neutrophil elastase may constitute a pathogenic link between these two pathologies. This was done in two animal models in which emphysema and fibrosis were induced either by bleomycin (Cavarra et al. ERJ , 2001) or cigarette-smoke (Bartalesi et al. ERJ, 2005). In particular, we demonstrate that in bleomycin-treated mice (i) the development of elastolytic emphysema precedes that of fibrosis; (ii) alveolar elastase burden is associated with an increased expression of transforming growth factor-β (TGF-β) and transforming growth factor-α (TGF-α); and finally, (iii) emphysematous and fibrotic lesions can be significantly attenuated by using an elastase inhibitor. Similarly, in mice that develop both emphysema and fibrosis after cigarette-smoke exposure an immunohistochemical reaction for elastase is associated with a positive reaction for TGF-β and TGF-α. These data indicate that neutrophil elastase represents a common pathogenic link between emphysema and fibrosis.
In conclusion, proteases and in particular elastase may constitute important regulatory factors in the generation of soluble cytokines with mitogenic activity for mesenchymal cells
Bleomycin induces emphysema in α-PI deficient mice
No full textIn a recent study we investigated in mice the role of a genetic deficiency of serum α-PI on the development of the pulmonary damage induced by the fibrogenic agent bleomycin (BLM). As expected BLM administration to mice resulted in alveolitis and fibrosis. It also resulted in enlargement of air spaces that may be due to loss of alveolar septa and/or retraction forces caused by the fibrotic process. In this study we investigated whether BLM induces air spaces enlargements of destructive type in strains of mice with a genetic deficiency of their antielastase screen. We used Balb/c mice with normal levels of serum α1-PI (5.9±0.5 mg/ml); C57Bl/6J, which show intermediate levels (4.4±0.3, p<0.05), and pallid mice with the lowest values (2.7±0.4 p<0.05). Mice from all strains received either saline (50μl), or BLM (0.1U/50μl) intratracheally and were sacrificed at 1, and 3, 14, 21 and 35 days after the treatment. The lungs were assessed by means of biochemical, morphological and morphometrical methods. At 14 days fibrosis affected 23.46 ± 9.48 % (mean ± S.D) and 40.62 ± 13.34 % (p<0.01) of the lungs of C57Bl/6J and pallid mice, respectively. At this time, air spaces enlargements affected 3.68 ± 3.11 % and 12.57 ± 4.13 % (p<0.01) of lung in C57Bl/6J and pallid mice, respectively. On the other hand, Balb c mice showed negligible foci of cellular infiltration and fibrosis (2±1%) and no areas of air-space enlargements. Pallid and C57 mice, 21h and 3 days after BLM, showed spotty areas of inflammatory cells infiltration and appreciable emphysematous changes. These changes that appeared long before the development of fibrosis, were associated with a decrease in lung desmosine content and an increase interstitial elastase burden. At 21 and 35 days after BLM, both the emphysematous and fibrotic lesions were more severe, and intermixed. At these times, the emphysematous changes became of paracicatricial type.
In conclusion, the data reported strongly suggest that the air-space enlargements observed in mice with a genetic deficiency of serum α-PI, early after BLM, represent areas of true emphysema caused by a proteolytic attack from infiltrating inflammatory cells. The further deterioration of these changes evident at the later times after BLM treatment can be ascribed to the retraction forces of the fibrotic process
Ongoing Lung Inflammation and Disease Progression in Mice after Smoking Cessation: Beneficial Effects of Formyl-Peptide Receptor Blockade
Full text linkThe most important risk factor for chronic obstructive pulmonary disease (COPD) is cigarette smoking. Until now, smoking cessation (SC) is the only treatment effective in slowing down the progression of the disease. However, in many cases SC may only relieve the airflow obstruction and inflammatory response. Consequently, a persistent lung inflammation in ex-smokers is associated with progressive deterioration of respiratory functions. This is an increasingly important clinical problem whose mechanistic basis remains poorly understood. Available therapies do not adequately suppress inflammation and are not able to stop the vicious cycle that is at the basis of persistent inflammation. In addition, in mice after SC an ongoing inflammation and progressive lung deterioration is observed. After 4 months of smoke exposure mice show mild emphysematous changes. Lung inflammation is still present after SC, and emphysema progresses during the next 6-month period of observation. Destruction of alveolar walls is associated with airways remodeling (goblet cell metaplasia and peribronchiolar fibrosis). Modulation of formyl-peptide receptor signaling with antagonists mitigates inflammation and prevents deterioration of lung structures. This study suggests an important role for N-formylated peptides in the progression and exacerbation of COPD. Modulating formyl-peptide receptor signal should be explored as a potential new therapy for COPD
Intratracheal f-MLP administration in mice reproduces smoke-induced pulmonary changes
No full textMucus hypersecretion and emphysema are important hallmarks of chronic obstructive lung disease. These changes may be induced in mice by chronic exposure to cigarette smoke (CS), however a different degree of sensitivity is observed in different strains of mice. In particular, C57Bl/6J mice, which are moderately deficient in serum alpha1-PI and sensitive to oxidants, develop after CS both goblet cell metaplasia (GCM) and emphysema, whereas DBA/2 mice, which are sensitive to oxidants, develop only emphysematous lesions. In previous studies we showed that the acute inflammatory effect induced by CS can be mimicked in C57BL/6J mice by i.tr. instillation of N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), a neutrophil chemotactic peptide. In this study we compared the pulmonary changes induced by fMLP in C57Bl/6J and DBA/2 mice. At 7 and 21days after a single administration of fMLP (200 mg), both strains developed pulmonary emphysema, but GCM appeared only in C57Bl/6J mice. Thus, in these strains pulmonary changes similar to those observed after CS can be elicited by fMLP administration. Strain characteristics (such as alpha1-PI levels, sensitivity to oxidants) and pheno- typical responses (apoptosis and cytokine distribution) may condition parenchymal and airway changes in response to fMLP. The knowledge of the interstrain variation in the lung response to fMLP may important for investigating the role of single factors in the pathogenesis of COPD. This model may be also useful for studying potential therapeutic agents
Effects of cigarette smoke on lung antioxidant defences, induction of goblet cell metaplasia and micropapillomatosis in DBA/2 and ICR mice
No full textThe role of strain differences in the response to cigarette smoke was investigated in mice. Basal total antioxidant capacity of bronchoalveolar lavage (BAL) fluids assessed as “Trolox equivalent antioxidant capacity” in DBA/2 mice was 61±12 nmolTrolox/ml BAL. After acute exposure to cigarette smoke (5 cigarettes within 20 min) the total BAL fluids antioxidant capacity of the DBA/2 mice decreased by 32% (p<0.01). Basal total antioxidant capacity of BAL fluids in ICR mice was similar to that of the DBA/2 mice (63±22 nmolTrolox/ml BAL). However, after acute cigarette smoke ICR mice increased their BAL antioxidant capacity by 57 % (p<0.01). Mice of these two strains were then exposed either to room air or to chronic cigarette smoke (3 cigarettes/day, 5 days/week) for 7 months. The animals were then sacrificed, the lungs stained with periodic acid-Schiff and the peripheral airways examined. The airways of both strains exposed to room air were normal. The peripheral airways of ICR mice exposed to cigarette smoke (N=5) showed no abnormalities and their epithelium was devoid of goblet cells. All DBA/2 mice exposed to cigarette smoke (N=8) exhibited a large number of goblet cells (goblet cell metaplasia) in their peripheral airways. Additionally, 7/8 mice had a diffuse micropapillomatosis in some cases with infiltrating character. All these results indicate that the response and sensitivity to the effects of cigarette smoke is strain-dependent
The Development of Cigarette Smoke-Induced Lung Lesions in Two Strains of Mice
No full textWe reported that ICR mice are resistant to chronic smoke while C57Bl/6J and DBA/2 mice develop emphysema. In this study we investigated the kinetics of cigarette smoke-induced emphysema and of airways changes in the two sensitive strains. C57Bl/6J and DBA/2 mice were exposed to either the smoke of 3 cigarettes/day (Virginia: 12 mg of tar and 0.9 mg of nicotine) 5 days/week for 1, 3, 6, 8, 10 and 12 months or to room air (controls). At these time intervals animals were sacrificed and the lungs assessed for emphysema (Lm, SA/VL) and for goblet cell metaplasia (GCM on PAS stained sections). Immunohistochemistry included MUC5AC, IL-4 and IL-13. Electron microscopy (EM) was also used. The percentage of C57Bl/6J mice with emphysema increased with time reaching 100% at 6 months and remained on this level. From 3 months onwards the Lm of the smoke exposed mice was greater and the SA/VL lower than in the controls. The percentage of DBA/2 mice with emphysema mice increased up to 6 months (83%) but decreased thereafter. At all time points the percentage of C57Bl/6J mice with emphysema was greater than that of DBA/2 mice. The percentage of C57Bl/6J mice with GCM increased from 40% at 1 month to 91% at 3 months and 100% at 6 months but decreased thereafter. In the DBA/2 group the percentage of mice with GCM was very low and occurred late (14% at 8 months and 25% at 10 months). In both strains in the responding animals there was a positive staining for IL-4, IL-13 and MUC 5 AC at 1, 3 and 8 months. Scanning EM showed areas of deciliation at 3 and 12 months in both strains. At transmission EM, the deciliated areas were characterized by de-differentiated cells with microvilli which have the potential to restore the normal epithelium. In apparently normally ciliated areas, a disorientation of the axonemal shaft was also observed.
Thus, there was a greater response of the C57Bl/6J mice both in terms of percentage of animals with emphysema and with GCM. In the affected animals the lesions were similar in both strains. Both strains are sensitive to cigarette oxidants but only C57BL/6J mice have low BAL elastase inhibitory capacity
Is there a pathogenic link between emphysema and fibrosis? Evidence from animal models.
No full textRecent data suggest that the separation of emphysema from fibrosis is not as clear-cut as it has appeared to be in early studies. In fact, both these pathologies may be present at the same time in human lungs, in lungs of mice after cigarette-smoke or bleomycin exposure, or in mouse lungs instilled with elastolytic enzymes. According to the current view, pulmonary emphysema originates from an imbalance between elastinolytic proteases and their inhibitors. Recently. a significant role for the antiproteases was also suggested in the modulation of fibrotic lesions.
We previously reported that BLM administration induced in α1-PI deficient mice alveolitis and fibrosis. It also resulted in enlargement of air spaces that may be due to loss of alveolar septa and/or retraction forces generated by the fibrotic process.
We recently demonstrated that the development of “true” elastolytic emphysema precedes that of fibrosis in α1-PI deficient mice. The further deterioration of these changes can be ascribed to the retraction forces of the fibrotic process. After BLM administration, we observed a significant change of a number of cytokines and cytokine receptors related to the neutrophil elastase activity. These cytokines were detected in foci of cellular proliferation and in areas of subpleural fibrosis when an increase of the elastase burden could be demonstrated.
A similar cytokine profile has been detected in mice that develop foci of subpleural fibrosis after cigarette-smoke.
In conclusion, proteases and in particular elastase may constitute important regulatory factors in the generation of soluble cytokines with mitogenic activity for mesenchymal cells
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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