tretinoin and Emphysema

The simplification of alveoli leads to various lung pathologies such as bronchopulmonary dysplasia and emphysema. Deep insight into the process of emergence of the secondary septa during development and regeneration after pneumonectomy, and into the contribution of the drivers of alveologenesis and neo-alveolarization is required in an efficient search for therapeutic approaches. In this review, we describe the formation of the gas exchange units of the lung as a multifactorial process, which includes changes in the actomyosin cytoskeleton of alveocytes and myofibroblasts, elastogenesis, retinoic acid signaling, and the contribution of alveolar mesenchymal cells in secondary septation. Knowledge of the mechanistic context of alveologenesis remains incomplete. The characterization of the mechanisms that govern the emergence and depletion of αSMA will allow for an understanding of how the niche of fibroblasts is changing. Taking into account the intense studies that have been performed on the pool of lung mesenchymal cells, we present data on the typing of interstitial fibroblasts and their role in the formation and maintenance of alveoli. On the whole, when identifying cell subpopulations in lung mesenchyme, one has to consider the developmental context, the changing cellular functions, and the lability of gene signatures.

Topics: Actomyosin; Bronchopulmonary Dysplasia; Cell Lineage; Cytoskeleton; Emphysema; Gases; Humans; Lung; Mesoderm; Myofibroblasts; Organogenesis; Pulmonary Alveoli; Tretinoin

A common feature of lung disorders with poor treatment options, including emphysema, is a failure to initiate a repair process of the alveolar epithelium. Several putative stem cell niches in the lung thought to be involved in lung homeostasis have been described. Apparently, under pathophysiological conditions these resident progenitor cells are unable to recover damaged alveolar epithelium, in particular in emphysema. The potential therapeutic effect of retinoic acid receptor agonists on various resident lung progenitor cells is reviewed.

Topics: Animals; Emphysema; Humans; Lung; Receptors, Retinoic Acid; Regeneration; Respiratory System Agents; Stem Cells; Treatment Outcome; Tretinoin

Classically, emphysema has been believed to develop when mediators of tissue injury exceed protective mechanisms within the lung. Evidence also supports the concept that tissue destruction represents a balance between tissue injury and tissue repair. In this context, cigarette smoke is directly toxic to cells within the lung and can impair the repair functions of fibroblasts, epithelial cells, and mesenchymal cells. This may occur in the absence of overt cytotoxicity and may result from alteration of selected biochemical pathways. A variety of repair functions can be affected, including chemotaxis, proliferation, production of extracellular matrix, and remodeling of extracellular matrix. Finally, cigarette smoke can damage DNA but can also compromise apoptosis. As a result, DNA repair mechanisms can be initiated, leading to recovery of cells that potentially contain somatic cell mutations. This pathway may contribute not only to the development of cancer but to the persistent abnormalities in tissue structure that characterize chronic obstructive pulmonary disease. Understanding the mechanisms that mediate normal tissue repair and understanding the bases for altered tissue repair in the face of cigarette smoking offer new opportunities designed to address the structural alterations that characterize chronic obstructive pulmonary disease.

Topics: Animals; Apoptosis; DNA Damage; DNA Repair; Emphysema; Humans; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Smoking; Tretinoin; Wound Healing

Recent data suggest that exogenous retinoic acid (RA), the biologically active derivative of vitamin A, can induce alveolar regeneration in a rat model of experimental emphysema. Here, we describe a mouse model of disrupted alveolar development using dexamethasone administered postnatally. We show that the effects of dexamethasone are concentration dependent, dose dependent, long lasting and result in a severe loss of alveolar surface area. When RA is administered to these animals as adults, lung architecture and the surface area per unit of body weight are completely restored to normal. This remarkable effect may be because RA is required during normal alveolar development and administering RA re-awakens gene cascades used during development. We provide evidence that RA is required during alveologenesis in the mouse by showing that the levels of the retinoid binding proteins, the RA receptors and two RA synthesizing enzymes peak postnatally. Furthermore, an inhibitor of RA synthesis, disulphiram, disrupts alveologenesis. We also show that RA is required throughout life for the maintenance of lung alveoli because when rats are deprived of dietary retinol they lose alveoli and show the features of emphysema. Alveolar regeneration with RA may therefore be an important novel therapeutic approach to the treatment of respiratory diseases characterized by a reduced gas-exchanging surface area such as bronchopulmonary dysplasia and emphysema for which there are currently no treatments.

Topics: Animals; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Emphysema; Humans; Mice; Morphogenesis; Pulmonary Alveoli; Receptors, Retinoic Acid; Regeneration; Signal Transduction; Tretinoin

In concert with its action as a morphogen during embryonal development, retinoic acid appears to be able to regenerate lung alveoli in an experimental model of elastase-induced emphysema in rats, thereby inhibiting manifestation of the disease. The application to humans is now an interesting possibility.

Topics: Animals; Emphysema; Humans; Pancreatic Elastase; Rats; Tretinoin

Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema.. One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 +/- 12.0% of predicted] and CT density mask (38.5 +/- 12.8% of voxels <- 910 Hounsfield units) [mean +/- SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period.. No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in Dlco (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild.. No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in Dlco, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.

Topics: Aged; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Emphysema; Feasibility Studies; Female; Humans; Isotretinoin; Keratolytic Agents; Male; Middle Aged; Quality of Life; Respiratory Function Tests; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Tretinoin

All-trans retinoic acid (ATRA) is controversially discussed in emphysema therapy. We re-evaluated ATRA in the elastase model and hypothesised that beneficial effects should be reflected by increased alveolar surface area, elastin expression and downregulation of inflammatory mediators and matrix metalloproteinases (MMPs). Emphysema was induced by porcine pancreatic elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 μg · kg(-1) body weight) versus olive oil. Lungs were removed at day 38. Rat alveolar epithelial L2 cells were incubated with/without elastase followed by ATRA- or vehicle-treatment, respectively. ATRA only partially ameliorated structural defects. Alveolar walls exhibited irregular architecture: increased arithmetic mean thickness, reduction in surface coverage by alveolar epithelial cells type II. ATRA only partially restored reduced soluble elastin. It tended to increase the ratio of ED1(+):ED2(+) macrophages. Bronchoalveolar lavage (BAL) cells exhibited a proinflammatory state and high expression of interleukin-1β, cytokine-induced neutrophil chemoattractant-1, tumour necrosis factor-α, nuclear factor-κB, MMP-2, MMP-9, MMP-12, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in emphysema, with ATRA exerting only few effects. MMP-7 was highly induced by ATRA in healthy but not in emphysematous lungs. ATRA reduced both MMP-2 and TIMP-1 activity in BAL fluid of emphysematous lungs. ATRA-therapy may bear the risk of unwanted side-effects on alveolar septal architecture in emphysematous lungs.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cell Line; Ectodysplasins; Elastin; Emphysema; Interleukin-1beta; Lung; Macrophages; Male; Matrix Metalloproteinase 12; Matrix Metalloproteinase 2; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Pancreatic Elastase; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tretinoin; Tumor Necrosis Factor-alpha

Granulocyte colony-stimulating factor (G-CSF) is known to mobilize stem cells to various organs and that it participates in tissue regeneration. Effect of the recombinant human G-CSF nartograstim (CAS 134088-74-7) was tested on elastase-induced emphysema. Porcine pancreas elastase (PPE) was administered intratracheally to male Sprague-Dawley rats to induce parenchymal destruction which was assessed by measuring the mean linear intercept (Lm) in tissue sections as an indicator of air space size. Lung alveoli were destructed and Lm value was significantly increased 2 weeks after PPE instillation. Increase in Lm was sustained for 8 weeks after PPE instillation. Two weeks after PPE instillation, 100 and 200 microg/kg of G-CSF injected for 5 d, followed by once and 3 injections a week for 5 weeks had reversed the increase in Lm by 28.7% (P = 0.02) and 35.2% (P = 0.004), respectively. Coadministration of 100 microg/kg x 5 injection of G-CSF with all-trans-retinoic acid (ATRA; 3 mg/ kg/d) for 3 weeks from 2 weeks after PPE instillation significantly inhibited the increase in Lm by 36% (p < 0.01), whereas administration of G-CSF or ATRA alone did not produce significant improvement. Preventive administration of G-CSF, which was treated for 4 weeks from 4 days after PPE instillation, did not improve enlargement of Lm. These data indicate that the administration of G-CSF is beneficial for the recovery of destructed alveoli.

Topics: Animals; Antineoplastic Agents; Emphysema; Granulocyte Colony-Stimulating Factor; Humans; Lung; Male; Pancreatic Elastase; Pulmonary Emphysema; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Regeneration; Swine; Tretinoin

Elastase-induced changes in lung morphology and function were detected in spontaneously breathing rats using conventional proton MRI at 4.7 T. A single dose of porcine pancreatic elastase (75 U/100 g body weight) or vehicle (saline) was administered intratracheally (i.t.) to male Brown Norway (BN) rats. MRI fluid signals were detected in the lungs 24 hr after administration of elastase and resolved within 2 weeks. These results correlated with perivascular edema and cellular infiltration observed histologically. Reductions in MRI signal intensity of the lung parenchyma, and increases in lung volume were detected as early as 2 weeks following elastase administration and remained uniform throughout the study, which lasted 8 weeks. Observations were consistent with air trapping resulting from emphysema detected histologically. In a separate experiment, animals were treated daily intraperitoneally (i.p.) with all-trans-retinoic acid (ATRA; 500 microg/kg body weight) or its vehicle (triglyceride oil) starting on day 21 after elastase administration and continuing for 12 days. Under these conditions, ATRA did not elicit a reversal of elastase-induced lung damage as measured by MRI and histology. The present approach complements other validated applications of proton MRI in experimental lung research as a method for assessing drugs in rat models of respiratory diseases.

Topics: Animals; Disease Models, Animal; Emphysema; Image Interpretation, Computer-Assisted; Lung; Magnetic Resonance Imaging; Male; Pancreatic Elastase; Prognosis; Protons; Rats; Respiratory Mechanics; Treatment Outcome; Tretinoin

Intratracheal administration of porcine pancreatic elastase (PPE) produced a dose related decline in lung function, as assessed by changes in dynamic lung compliance (C(dyn)) in New Zealand White rabbits. This occurred within 24 h of administration and persisted for 56 days (n=6). These lung function changes were accompanied by histological evidence of emphysema in the lungs and were not mimicked by intratracheal administration of the proteolytic enzyme trypsin. Neither the lung function nor the histological changes induced by elastase could be prevented or reversed by either the glucocorticosteroid, dexamethasone, or all trans retinoic acid (ATRA).Our data suggest that local administration of elastase to the lungs of rabbits may provide a convenient way to assess the effects of drugs on the changes induced by elastase in airways.

Topics: Animals; Antineoplastic Agents; Dexamethasone; Emphysema; Glucocorticoids; Male; Pancreatic Elastase; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Rabbits; Swine; Treatment Failure; Tretinoin

This study was designed to test the hypothesis that cigarette smoke-induced inflammation and emphysema are amplified by the presence of latent adenoviral (Ad) infection, and to determine whether this emphysematous process can be reversed by all-trans-retinoic acid (RA) treatment. The results confirm that in guinea pigs, chronic cigarette-smoke exposure caused lesions similar to human centrilobular emphysema. They also show that latent Ad infection combined with cigarette-smoke exposure caused an excess increase in lung volume (P < 0.001), air-space volume (P < 0.001), and lung weight (P < 0.01), and further decrease in surface-to-volume ratio (P < 0.001) compared with smoke exposure alone. RA treatment failed to reverse these emphysematous changes. Analysis of inflammatory response in parenchymal and airway tissue showed that smoking caused an increase of polymorphonuclear leukocytes (PMNs) (P < 0.0002), macrophages (P < 0.001), and CD4 cells (P < 0.0009), and that latent Ad infection independently increased PMNs (P < 0.001), macrophages (P = 0.003), and CD8 cells (P < 0.001). We conclude that latent Ad infection amplifies the emphysematous lung destruction and increases the inflammatory response produced by cigarette-smoke exposure. In this study, the increase in CD4 was associated with cigarette smoke and the increase in CD8 cells with latent Ad infection.

Topics: Adenoviridae; Analysis of Variance; Animals; Body Weight; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chromatography, High Pressure Liquid; Emphysema; Female; Guinea Pigs; Inflammation; Lung; Macrophages; Neutrophils; Organ Size; Smoking; Tretinoin

Proteolytic degradation of extracellular matrix is thought to play an important role both in emphysema and in tissue development and repair. Retinoic acid has been suggested to modify tissue injury, and in an animal model of emphysema may induce alveolar repair. Since cytokines can induce matrix metalloproteinase (MMP) production in fibroblasts and neutrophil elastase (NE) can activate MMPs, we hypothesized that retinoic acid could attenuate collagen degradation by modifying MMP production and activation. To evaluate this, human lung fibroblasts were cast into native type I collagen gels and floated in medium containing cytomix (TNF-alpha, IL-1beta, and IFN-gamma) alone or in combination with NE in the presence and absence of retinoic acid (1 microM). After 5 d, cytomix with elastase induced significant degradation of the collagen gels assessed by quantifying total hydroxyproline (41.6 +/- 1.6 microg versus 3.3 +/- 1.5 microg, P < 0.01). Retinoic acid significantly inhibited this degradation (23.3 +/- 1.5 microg versus 3.3 +/- 1.5 microg, P < 0.01). Gelatin zymography and Western blot revealed that MMP-1, MMP-3, and MMP-9 were induced by cytomix and that co-exposure to NE resulted in increased production of activated forms of these enzymes. Retinoic acid attenuated the induction and activation of MMP-1 and MMP-3. The current study, therefore, suggests that in addition to stimulating anabolic effects, retinoic acid may modulate proteolytic processes thought to contribute to tissue destruction in emphysema.

Topics: Animals; Antineoplastic Agents; Cell Culture Techniques; Cells, Cultured; Collagen Type I; Cytokines; Emphysema; Enzyme Activation; Extracellular Matrix; Fibroblasts; Gelatin; Gels; Humans; Interferon-gamma; Interleukin-1; Leukocyte Elastase; Lung; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Rats; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tretinoin; Tumor Necrosis Factor-alpha

Pulmonary alveoli are formed in part by subdivision (septation) of the gas-exchange saccules of the immature lung. Septation results in smaller, more numerous structures (alveoli) and is developmentally regulated in mammals including humans, rats, and mice; if it fails to occur at the appropriate time, there is no spontaneous post hoc septation nor has there been a means of inducing septation after it has failed to occur. We measured lung volume, the volume of individual alveoli, and alveolar surface area and calculated alveolar number in neonatal rats in which septation had been blocked by treatment with a glucocorticosteroid hormone and in adult tight-skin mice that have a genetic failure of septation. We tested the hypothesis that treatment with all-trans retinoic acid induces post hoc septation. In both models of failed septation, hence in two species, and in immature and adult animals, treatment with all-trans retinoic acid induced post hoc septation, offering the possibility of a similar effect in premature infants.

Topics: Animals; Antineoplastic Agents; Dexamethasone; Emphysema; Female; Glucocorticoids; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Organ Size; Pregnancy; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Specific Pathogen-Free Organisms; Tretinoin

Topics: Animals; Emphysema; Humans; Tretinoin

Topics: Animals; Cricetinae; Emphysema; Hyaluronic Acid; Lung Diseases; Macrophage Activation; Macrophages, Alveolar; Trachea; Tretinoin