Progressive Collagen Deposition Research Articles

Juvenile Systemic Scleroderma: A comprehensive Review and Clinical Case Report from a Tertiary Care Hospital in India

Juvenile systemic sclerosis (JSSc) is a highly uncommon, chronic connective tissue disorder that affects multiple systems, marked by progressive deposition of collagen under the dermis, and various deep organs. Delay in diagnosis can cause irreversible vital organ damage, leading to severe morbidities and seriously affecting quality of life. We report a clinical case of a 9-year-old boy with extensive and diffuse skin manifestations with vascular, pulmonary, and gastrointestinal involvement. The sero-immunological test revealed positive ANA results and high titers of anti-topoisomerase (Scl-70) antibodies, indicative of severe manifestation of the disease. He was managed with systemic immunosuppression and other pharmacological and rehabilitative measures to prevent ongoing organ damage and alleviate the patient’s symptoms.

High frequencies of vitamin B12 and folic acid deficiencies and hyperhomocysteinemia in Taiwanese male patients with oral submucous fibrosis

Background/purpose: Oral submucous fibrosis (OSF) is a betel quid chewing-caused oral mucosal disease with progressive collagen deposition. This study evaluated whether Taiwanese male OSF patients had high frequencies of vitamin B12 and folic acid deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity. Materials and methodsThe blood hemoglobin (Hb), serum iron, vitamin B12, folic acid, homocysteine, and GPCA concentrations in 62 male OSF patients were measured and compared with the corresponding data in 124 age-matched male healthy control subjects. ResultsWe found that 5 (8.1%), 12 (19.4%), 32 (51.6%), 31 (50.0%), 22 (35.5%), and 6 (9.7%) of the 62 male OSF patients had Hb (<13 g/dL), iron (≤70 μg/dL), vitamin B12 (≤450 pg/mL), and folic acid (≤6 ng/mL) deficiencies, hyperhomocysteinemia (>12 μM), and serum GPCA positivity, respectively. Furthermore, OSF patients had significantly higher frequencies of Hb (P = 0.006), vitamin B12 (P < 0.001), and folic acid (P < 0.001) deficiencies, hyperhomocysteinemia (P < 0.001), and serum GPCA positivity (P = 0.030) than 124 healthy control subjects. Of the 22 OSF patients with hyperhomocysteinemia, 4 had vitamin B12 deficiency only, 7 had folic acid deficiency only, and 11 had both vitamin B12 and folic acid deficiencies. ConclusionWe conclude that Taiwanese male OSF patients have high frequencies of vitamin B12 and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity. The hyperhomocysteinemia in our OSF patients is predominantly due to deficiencies of either vitamin B12 or folic acid or both.

Decellularized biologic muscle-fascia abdominal wall scaffold graft

BackgroundComplex abdominal wall reconstruction using biologic mesh can lead to increased recurrence rates, nonincorporation, and high perioperative costs. We developed a novel decellularization method and applied it to porcine muscle fascia to mirror target-tissue architecture. The aims of this study were to analyze mechanical strength and tissue-graft incorporation. MethodsAfter serial decellularization, muscle-fascia mesh was created and tested for mechanical strength and DNA content. The muscle-fascia mesh was implanted subcutaneously in rats (n = 4/group) and the cohorts killed 1 to 4 weeks later. Explants were examined histologically or immunohistochemically. ResultsMechanical testing demonstrated equivalent strength compared with a commercially available biological mesh (AlloDerm), with mechanical strength attributable to the fascia component. Grafts were successfully implanted with no observable adverse events. Gross necroscopy revealed excellent subdermal scaffold engraftment. Microscopic evaluation identified progressive collagen deposition within the graft, neoangiogenesis, and presence of CD34 positive cells, in the absence of discernable graft rejection. ConclusionThis study confirms a decellularization process can successfully create a DNA-free composite abdominal wall (muscle-fascia) scaffold that can be implanted intraspecies without rejection. Expanding this approach may allow exploitation of the angiogenic capacities of decellularized muscle, concomitant with the inherent strength of decellularized fascia, to perform preclinical analyses of graft strength in animal models in vivo.

New mouse model of underactive bladder developed by placement of a metal ring around the bladder neck.

To develop a new mouse model of underactive bladder (UAB) caused by chronic bladder outlet obstruction (BOO). BOO was created in 6-week-old male C57BL/6 mice using surgery to loosely place a silver jump ring around the bladder neck of each mouse. Micturition behavior (assessed with a metabolic cage) and cystometry were used to evaluate bladder function at 8 and 16 weeks after BOO. Following completion of the functional studies, the bladders of the mice were excised, weighed, and subjected to histological analysis. Micturition behavior analysis showed that mice subjected to BOO for 16 weeks had a lower frequency of micturition (7.3 ± 1.1 vs 12.5 ± 3.0 times/d, P < .05) and volume per void (106.0 ± 0.1 vs 133.9 ± 3.2 μL, P < .05) than mice subjected to BOO for 8 weeks. Cystometry revealed that mice subjected to BOO for 16 weeks had lower baseline pressure (8.4 ± 0.6 vs 14.0 ± 0.7 cmH2 O, P < .01) and micturition pressure (13.9 ± 1.1 vs 42.8 ± 1.7 cmH2 O, P < .05) than mice subjected to BOO for 8 weeks. BOO caused progressive increases in bladder mass and collagen deposition over time. We successfully established a novel mouse model of UAB using surgery to place a silver jump ring loosely on the bladder neck. BOO initially induced bladder overactivity but subsequently resulted in UAB due to deterioration of detrusor smooth muscle contractility and progressive deposition of collagen in the bladder wall.

Benefits of extracorporeal shock waves for keloid treatment: A pilot study

Keloids are fibroproliferative skin disorders characterized by the progressive deposition of collagen. Recently, extracorporeal shock wave therapy (ESWT) has been used to treat pathologic scars. Herein, we conducted a study to compare the efficacy of intralesional injections (ILIs) of triamcinolone acetonide (TA) used alone, or in combination with ESWT for keloids. Forty patients were randomized equally into two groups in this 12-week comparative clinical trial. Group A was treated with TA ILIs and ESWT, and group B was treated with TA ILIs alone. At week 12, both groups showed acceptable improvements in nearly all dimensions evaluated, and these improvements were statistically more significant in group A. Group A showed a higher mean percentage reduction in lesion length, width, and height and in the Vancouver Scar Scale score than group B (all P < .05). More patients in group A than in group B had scores of ≥4, which indicated improvements that were good or excellent, on the patient global assessment and investigator global assessment. No serious adverse events occurred. This study suggests that ESWT could be a new, effective and acceptable adjuvant treatment option for keloids.

Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice.

A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). C57BL/6J mice have been exposed to room air or cigarette smoke up to 11months and killed at different time points. Functional and molecular studies have been performed. Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

In vivo label-free optical monitoring of structural and metabolic remodeling of myocardium following infarction.

Cardiac remodeling following myocardial infarction (MI) involves structural and functional alterations in the infarcted and remote viable myocardium that can ultimately lead to heart failure. The underlying mechanisms are not fully understood and, following our previous study of the autofluorescence lifetime and diffuse reflectance signatures of the myocardium in vivo at 16 weeks post MI in rats [Biomed. Opt. Express 6(2), 324 (2015)25780727], we here present data obtained at 1, 2 and 4 weeks post myocardial infarction that help follow the temporal progression of these changes. Our results demonstrate that both structural and metabolic changes in the heart can be monitored from the earliest time points following MI using label-free optical readouts, not only in the region of infarction but also in the remote non-infarcted myocardium. Changes in the autofluorescence intensity and lifetime parameters associated with collagen type I autofluorescence were indicative of progressive collagen deposition in tissue that was most pronounced at earlier time points and in the region of infarction. In addition to significant collagen deposition in infarcted and non-infarcted myocardium, we also report changes in the autofluorescence parameters associated with reduced nicotinamide adenine (phosphate) dinucleotide (NAD(P)H) and flavin adenine dinucleotide (FAD), which we associate with metabolic alterations throughout the heart. Parallel measurements of the diffuse reflectance spectra indicated an increased contribution of reduced cytochrome c. Our findings suggest that combining time-resolved spectrofluorometry and diffuse reflectance spectroscopy could provide a useful means to monitor cardiac function in vivo at the time of surgery.

From genetics to epigenetics: new insights into keloid scarring.

Keloid scarring is a dermal fibroproliferative response characterized by excessive and progressive deposition of collagen; aetiology and molecular pathology underlying keloid formation and progression remain unclear. Genetic predisposition is important in the pathogenic processes of keloid formation, however, environmental factors and epigenetic mechanisms may also play pivotal roles. Epigenetic modification is a recent area of investigation in understanding the molecular pathogenesis of keloid scarring and there is increasing evidence that epigenetic changes may play a role in induction and persistent activation of fibroblasts in keloid scars. Here we have reviewed three epigenetic mechanisms: DNA methylation, histone modification and the role of non-coding RNAs. We also review the evidence that these mechanisms may play a role in keloid formation - in future, it may be possible that epigenetic markers may be used instead of prognostic or diagnostic markers here. However, there is a significant amount of work required to increase our current understanding of the role of epigenetic modification in keloid disease.

Redefining epithelial characterization in oral submucous fibrosis using morphometric analysis

Background:Oral submucous fibrosis (OSMF) is a chronic oral mucosal disease characterized by progressive deposition of collagen in subepithelial connective tissue and epithelial atrophy. The present study was conducted to evaluate the changes in epithelial thickness and cellular and nuclear morphometric characteristics of parabasal and spinous compartments of the epithelium in various stages of OSMF in comparison to normal epithelium.Materials and Methods:Sample included 30 cases of OSMF of various stages and five cases of normal buccal mucosa. Measurements for epithelial thickness and cellular morphology using morphometric analysis were performed on captured digital images using image analysis software.Statistical Analysis:The ANOVA analysis of epithelial thickness and correlation of epithelial thickness with cell contour and cell roundness was done using Karl Pearson's coefficient of correlation.Results:There was a statistically significant decrease in epithelial thickness with increase in severity/stage of OSMF. It was also observed that there is a highly statistically significant correlation (P = 0.000) between the thickness of epithelium and cell morphology in varying stages of OSMF.Conclusion:The morphometric parameters and the use of quantitative histological methods in determining the squamous epithelial structures thus made it possible to evaluate that there is reduction in thickness of epithelium or “atrophy” with increasing stages of OSMF which may be due to actual change in cell morphology of the individual cells of specific compartment or all compartments in the epithelium.

CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis.

The calcium and calmodulin-dependent kinase II (CaMKII) translates increases in intracellular Ca(2+) into downstream signaling events. Its function in pulmonary pathologies remains largely unknown. CaMKII is a well-known mediator of apoptosis and regulator of endoplasmic reticulum (ER) Ca(2+). ER stress and apoptosis of type II pneumocytes lead to aberrant tissue repair and progressive collagen deposition in pulmonary fibrosis. Thus we hypothesized that CaMKII inhibition alleviates fibrosis in response to bleomycin by attenuating apoptosis and ER stress of type II pneumocytes. We first established that CaMKII was strongly expressed in the distal respiratory epithelium, in particular in surfactant protein-C-positive type II pneumocytes, and activated after bleomycin instillation. We generated a novel transgenic model of inducible expression of the CaMKII inhibitor peptide AC3-I limited to type II pneumocytes (Tg SPC-AC3-I). Tg SPC-AC3-I mice were protected from development of pulmonary fibrosis after bleomycin exposure compared with wild-type mice. CaMKII inhibition also provided protection from apoptosis in type II pneumocytes in vitro and in vivo. Moreover, intracellular Ca(2+) levels and ER stress were increased by bleomycin and significantly blunted with CaMKII inhibition in vitro. These data demonstrate that CaMKII inhibition prevents type II pneumocyte apoptosis and development of pulmonary fibrosis in response to bleomycin. CaMKII inhibition may therefore be a promising approach to prevent or ameliorate the progression of pulmonary fibrosis.

Pathobiology of HIV/SIV-associated changes in secondary lymphoid tissues.

Acquired immunodeficiency syndrome (AIDS) is principally a disease of lymphoid tissues (LTs), due to the fact that the main target cell of human immunodeficiency virus (HIV) is the CD4(+) T lymphocyte that primarily resides within organs of the immune system. The impact of HIV infection on secondary LTs, in particular lymph nodes, is critical to delineate, as these immune organs are the principal sites for initiating and facilitating immune responses and are critical for lymphocyte homeostatic maintenance and survival. The underlying structural elements of LTs, fibroblastic reticular cell (FRC) network, not only form the architectural framework for these organs, but also play in integral role in the production and storage of cytokines needed for T-cell survival. There is an interdependent relationship between the FRC stromal network and CD4(+) T lymphocytes for their survival and maintenance that is progressively disrupted during HIV disease. HIV infection results in profound pathological changes to LTs induced by persistent chronic immune activation and inflammation that leads to progressive collagen deposition and fibrosis disrupting and damaging the important FRC network. In this review, I focus on the process, mechanisms, and the implications of pathological damage to important secondary LTs, combining what we have learned from HIV-infected individuals as well as the invaluable knowledge gained from studies in non-human primate simian immunodeficiency virus infection models.

Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model

To investigate whether transforming growth factor-β1 (TGF-β1) signaling pathway is involved in the pathogenesis of primary biliary cirrhosis (PBC). A murine model of PBC was developed by injection of polyinosinic polycytidylic acids (poly I: C) in C57BL/6 mice, and the liver expressions of TGF β1, TGF-β receptor I (TβRI), TGF-β receptor II (TβRII), p-Smad2/3, monoclonal α-smooth muscle actin antibody (α-SMA) and α1 (I) collagen in the mouse model and control mice were evaluated by immunohistochemistry, immunoblotting and real-time polymerase chain reaction (RT-PCR). Lymphocyte subsets in liver were analyzed using flow cytometry. The mouse model had several key phenotypic features of human PBC, including elevated levels of alkaline phosphatase, antimitochondrial antibodies, portal bile ducts inflammation, and progressive collagen deposition. Compared with control mice, protein and mRNA levels of TGF β1, TβRI, TβRII, p-Smad2/3, α-SMA and α1 (I) collagen in liver (1.7 ± 0.4 vs 8.9 ± 1.8, 0.8 ± 0.2 vs 5.1 ± 1.5, 0.6 ± 0.01 vs 5.1 ± 0.1, 0.6 ± 0.3 vs 2.0 ± 0.3, 0.9 ± 0.4 vs 3.4 ± 0.6, 0.8 ± 0.4 vs 1.7 ± 0.3, 1.1 ± 1.2 vs 11.8 ± 0.6, P < 0.05), and the total number and percentage of CD4⁺ CD25⁺ FOXP3⁺ and CD8⁺ lymphocytes (0.01 ± 0.001 vs 0.004 ± 0.00, 0.12 ± 0.04 vs 0.52 ± 0.23, P < 0.01) were higher in the mouse model. TGFβ1 might play a dual role in the development of PBC: it suppresses inflammatory response but operates to enhance fibrogenesis. The aberrant activity of TGF-β1 signaling contributes to the development of PBC.

Dynamics of Capillaria-hepatica-induced hepatic septal fibrosis in rats

The pathogenesis of septal hepatic fibrosis, induced in rats by Capillaria hepatica infection, was studied with the aid of a large collection of stored paraffin blocks, representative of the different evolutive phases of fibrosis which appeared in 100% of infected rats. Studies were conducted involving histology, immunohistochemistry, immunofluorescence and morphometric methods, in order to observe the dynamic behavior of the cellular and matrix components of fibrosis, over a one year period of evolution. Observation verified that septal fibrosis originates from several portal spaces simultaneously. Its origin and progression involve blood vessel proliferation (angiogenesis), multiplication of actin-positive cells (pericytes and myofibroblasts) and progressive collagen deposition. By the end of 4-5 months, a progressive decrease in all these components was observed, when signs of regression of septal fibrosis became more evident over time. Besides indicating the fundamental role played by angiogenesis in the pathogenesis of fibrosis, these morphological data concerning the dynamics of this C. hepatica experimental model proved to be adequate for future investigations regarding the functional aspects of fibrosis induction, progression and regression.

Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis.

The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Here, the experimental evidence supporting the participation of various growth factors in the pathogenesis of the fibrotic process in SSc and the molecular mechanisms involved will be reviewed.

Impact of successful and failed revascularization of chronic total occlusion on left ventricular function and infarct size

Introduction Non-randomised studies have reported a prognostic advantage with percutaneous coronary intervention (PCI) in the treatment of chronic total occlusions (CTO). Failure to cross and successfully open a CTO confers a worse clinical outcome, however most trials have included occlusions of short duration (7-30 days). PCI success rates are inversely related to the age of vessel occlusion reflecting temporal, cellular changes within a CTO, namely progressive collagen deposition.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with different types of scars and keloids

Hypertrophic scars and keloids are fibroproliferative skin disorders characterised by progressive deposition of collagen. Our study is designed to investigate the expression and concentration of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in different types of scars and keloids. Total RNA from 19 proliferative hypertrophic scar samples of patients with extended burns (total body surface area (TBSA): 21+/-12%), 18 mature hypertrophic scar samples from patients after elective surgery, 14 keloid samples and 18 normotrophic scar samples was, respectively, extracted, and then mRNA was isolated. Besides, biopsies were obtained from non-scarred skin of the patients and extraction of total RNA performed. Relative mRNA expression of MMP 2, MMP 9, TIMP 1 and TIMP 2 was measured with reverse transcriptase polymerase chain reaction (RT-PCR). Serum concentrations of MMP-1, -2, -9, TIMP-1, and -2 were determined using an enzyme-linked immunosorbent assay (ELISA). Patients with extended hypertrophic scars after burn trauma presented a significantly higher TIMP-1 concentration (p<0.05) in their sera than the other patients. The relative expression of MMP 2 was significantly higher in samples of proliferative hypertrophic scars after burn injury. The relative expression of TIMP 1 and TIMP 2 was significantly higher in scar tissue of patients with proliferative and mature hypertrophic scars and keloids than in their regular skin and in scar samples of patients with normotrophic scars. The expression of TIMP 1 was significantly higher in samples of patients with keloids than in patients with hypertrophic scars. The concentration of TIMP-1 in sera of patients varies depending on the size of the involved fibrotic scar tissue. A decrease in MMP-to-TIMP expression in scar tissue may contribute to increased synthesis and deposition of collagen, leading to a severe fibrotic reaction with pathologic scar formation. The results implicate non-operative therapy options in these patients that not only down-regulate TIMPs but also increase the activity of MMPs.

Direct Renin Inhibition

The process of cardiac healing and recovery after an acute myocardial infarction encompasses profound changes in the necrotic area (“infarct zone”), in the neighboring ischemic zone (“area at risk”), and in the nonischemic myocardium (“nonischemic region”). Patient’s prognosis ultimately depends on the functional, biochemical, electric, and structural changes taking place in these 3 different areas as a consequence of the acute ischemic event. These extracellular, cellular, and subcellular events are globally referred to as “postinfarction remodeling,” and therapeutic interventions able to slow or reverse its progression have a favorable impact on patient prognosis.1 A pivotal role in these processes is played by the renin-angiotensin-aldosterone system (RAAS) that is undoubtedly hyperactivated after myocardial infarction, together with other neural and endocrine systems. Locally synthesized angiotensin II has been suggested to act as an autocrine, paracrine, and intracrine modulator of cardiac function.2 Notably, the major components of the RAAS components have been shown in cardiac tissue, and extracardiac renin uptake is associated with local release by myocardial mast cells.3 Angiotensin II intracellular signal transduction involves the phosphorylation of several proteins, such as membrane transporters and selective ion channels, structural and contractile proteins, and enzymes that regulate metabolism, protein synthesis, and gene expression. These multiple actions are mediated via complex intracellular signaling pathways, including stimulation of the phospholipase C-inositol 1,4,5-trisphosphate-1,2-diacylglycerol cascade, mitogen-activated protein kinases, tyrosine kinases, RhoA/Rho kinase, and reactive oxygen species generation through vascular NADPH oxidase activation. Beyond directly affecting vasomotor tone, angiotensin II potentiates the effects of several vasoconstrictor hormones, facilitates the central and …

Myostatin Directly Regulates Skeletal Muscle Fibrosis

Skeletal muscle fibrosis is a major pathological hallmark of chronic myopathies in which myofibers are replaced by progressive deposition of collagen and other extracellular matrix proteins produced by muscle fibroblasts. Recent studies have shown that in the absence of the endogenous muscle growth regulator myostatin, regeneration of muscle is enhanced, and muscle fibrosis is correspondingly reduced. We now demonstrate that myostatin not only regulates the growth of myocytes but also directly regulates muscle fibroblasts. Our results show that myostatin stimulates the proliferation of muscle fibroblasts and the production of extracellular matrix proteins both in vitro and in vivo. Further, muscle fibroblasts express myostatin and its putative receptor activin receptor IIB. Proliferation of muscle fibroblasts, induced by myostatin, involves the activation of Smad, p38 MAPK and Akt pathways. These results expand our understanding of the function of myostatin in muscle tissue and provide a potential target for anti-fibrotic therapies.

Thrombus organization and healing in the swine experimental aneurysm model. Part I. A histological and molecular analysis

The authors describe the process of thrombus organization in the swine surgical aneurysm model. Lateral carotid artery aneurysms with immediately induced thrombosis were created in 31 swine for a time-course study. Aneurysms were evaluated at 1, 3, 7, 14, 30, and 90 days after they were created. Histological analyses included quantitative immunohistochemical studies and evaluation of collagen deposition. Complementary DNA microarray analysis was performed for gene expression profiling. The lists of up- and downregulated genes were cross-matched with lists of genes known to be associated with cytokines or the extracellular matrix. The expression of selected genes was quantified using real-time polymerase chain reaction. Functional clustering was performed with the Expression Analysis Systematic Explorer (EASE) bioinformatics package. Histological analysis demonstrated leukocyte and macrophage infiltration in the thrombus at Day 3, myofibroblast infiltration at Days 7 to 14, and progressive collagen deposition and contraction thereafter. Tissue organization occurred in a centripetal fashion. A previously undescribed reticular network of connective tissue was observed at the periphery of the aneurysm at Day 3. Macrophages appeared critical to this thrombus organization. A total of 1109 genes were significantly changed from reference time zero during the time course: CXCL14, which produces a monocyte-specific chemokine, was upregulated over 100-fold throughout the time course; IGF1 was upregulated fourfold at Day 7, whereas IGFBP2 was downregulated approximately 50% at Days 7 and 14. Osteopontin (SPP1) upregulation increased from 30-fold at Day 30 to 45-fold at Day 14. The EASE analysis yielded eight functional classes of gene expression. This investigation provides a detailed histological and molecular analysis of thrombus organization in the swine aneurysm model. The companion study will describe the effect of embolic bioabsorbable polymers on this process.

Lung Fibrotic Responses to Particle Exposure

Particles generated from numerous anthropogenic sources have the potential to cause or exacerbate lung diseases, including asthma, bronchitis, and COPD. Fibrotic reactions are a component of all of these pulmonary diseases, and involve the progressive deposition of collagen by pulmonary fibroblasts. The reactivity, toxicity, and fibrogenic potential of particles in the lung depends on a variety of factors including particle size, surface area, and composition. Smaller particles, particularly in the nanosized range, have more toxic and fibrogenic capacity due to a higher surface-to-mass ratio and greater oxidant-generating potential. Composition is also an important determinant in the fibrotic response to particles. Transition metals, bacterial lipopolysaccaride, and polycyclic aromatic hydrocarbons are some of the toxic components of particles that activate intracellular signaling pathways that culminate in the production of profibrotic cytokines and growth factors.