Focal Fibrotic Lesions Research Articles

Distinguishing 320 slice CT-detected focal fibrotic lesions and non-fibrotic lesions in hypertrophic cardiomyopathy by assessment of regional myocardial strain using two dimensional speckle tracking echocardiography

Distinguishing 320 slice CT-detected focal fibrotic lesions and non-fibrotic lesions in hypertrophic cardiomyopathy by assessment of regional myocardial strain using two dimensional speckle tracking echocardiography

Strain-dependent Damage in Mouse Lung After Carbon Ion Irradiation

To examine whether inherent factors produce differences in lung morbidity in response to carbon ion (C-ion) irradiation, and to identify the molecules that have a key role in strain-dependent adverse effects in the lung. Three strains of female mice (C3H/He Slc, C57BL/6J Jms Slc, and A/J Jms Slc) were locally irradiated in the thorax with either C-ion beams (290 MeV/n, in 6 cm spread-out Bragg peak) or with ¹³⁷Cs γ-rays as a reference beam. We performed survival assays and histologic examination of the lung with hematoxylin-eosin and Masson's trichrome staining. In addition, we performed immunohistochemical staining for hyaluronic acid (HA), CD44, and Mac3 and assayed for gene expression. The survival data in mice showed a between-strain variance after C-ion irradiation with 10 Gy. The median survival time of C3H/He was significantly shortened after C-ion irradiation at the higher dose of 12.5 Gy. Histologic examination revealed early-phase hemorrhagic pneumonitis in C3H/He and late-phase focal fibrotic lesions in C57BL/6J after C-ion irradiation with 10 Gy. Pleural effusion was apparent in C57BL/6J and A/J mice, 168 days after C-ion irradiation with 10 Gy. Microarray analysis of irradiated lung tissue in the three mouse strains identified differential expression changes in growth differentiation factor 15 (Gdf15), which regulates macrophage function, and hyaluronan synthase 1 (Has1), which plays a role in HA metabolism. Immunohistochemistry showed that the number of CD44-positive cells, a surrogate marker for HA accumulation, and Mac3-positive cells, a marker for macrophage infiltration in irradiated lung, varied significantly among the three mouse strains during the early phase. This study demonstrated a strain-dependent differential response in mice to C-ion thoracic irradiation. Our findings identified candidate molecules that could be implicated in the between-strain variance to early hemorrhagic pneumonitis after C-ion irradiation.

Anthracofibrosis Involving Lung Parenchyma

To describe computed tomographic (CT) findings of anthracofibrosis involving lung parenchyma. Retrospectively reviewed CT findings of 34 patients with anthracofibrosis involving lung parenchyma, showing deposition of anthracotic pigmentation with focal fibrotic lesions on histologic examination. Types included nodules (41.2%), masses (55.9%), and fibrotic consolidation (2.9%). The mean size was 26.8 mm. The most common location was right upper lobe (n = 10). Satellite nodules were identified in 5 patients, calcification was identified in 11 patients, necrotic low attenuation was identified in 9 patients, and marginal spicule was identified in 26 patients (76.5%). The CT images showed airway manifestation of anthracofibrosis in 13 patients, nodal manifestation in 11 patients, and inactive tuberculosis in 14 patients. Initial radiologic diagnosis included tuberculosis (n = 10), lung cancer (n = 9), organized pneumonia (n = 7), nonspecific pulmonary nodule (n = 7), and anthracofibrosis (n = 1). Anthracofibrosis involving lung parenchyma appears as a nodule, mass, or fibrotic consolidation, surrounded by long spicule. It may be the spectrum of bronchial anthracofibrosis involving small airway of lung parenchyma.

Distinguishing focal fibrotic lesions and non-fibrotic lesions in hypertrophic cardiomyopathy by assessment of regional myocardial strain using two-dimensional speckle tracking echocardiography: Comparison with multislice CT

PurposeTo distinguish focal fibrotic and non-fibrotic lesions in left-ventricular myocardium (LVM) in hypertrophic-cardiomyopathy (HCM)-subjects, we compared myocardial regional peak-strain values using two-dimensional speckle-tracking transthoracic-echocardiography (TTE) in multislice computed-tomography (CT)-detected fibrotic, non-fibrotic and normal control lesions. MethodsTwenty subjects (10 consecutive HCM-subjects (8-males, mean 63.4-years), 10 healthy controls (5-males, mean 51.5-years)) underwent speckle-tracking TTE (iE-33), and analysis of regional peak-longitudinal (LS) and radial-strain (RS), and corresponding strain rates in each of 17 LVM segments (American-Heart-Association classification). In HCM-subjects, fibrotic lesions were identified by early-phase defective enhancement and late-phase abnormal enhancement by CT (Light-Speed-Ultra-16). Regional peak LS and RS at basal, mid and apical levels were measured in MSCT-detected fibrotic and non-fibrotic LVM lesions. ResultsIn 10 HCM subjects, 143 lesions (84.1%) yielded good tracking on TTE. Twenty lesions showed fibrotic changes in 5 subjects by CT.Regional peak-LS and RS absolute values were significantly lower in both fibrotic and non-fibrotic lesions in HCM subjects than in controls at basal, mid, apical levels (all P<0.05). While peak-LS (%) absolute values were significantly lower in fibrotic than non-fibrotic lesions at basal, mid and apical levels (all P<0.05), regional peak-RS absolute values were significantly lower only at mid levels. LS was a more sensitive indicator than the corresponding rate, with better reproducibility. ConclusionsIn HCM, regional peak-LS was significantly lower in fibrotic than non-fibrotic lesions in LVM by CT. Regional peak-LS by speckle-tracking provides useful information noninvasively to distinguish fibrotic from non-fibrotic lesions in LVM in HCM and normal LVM in healthy controls.

Identifying the High Radiosensitivity of the Lungs of C57L Mice in a Model of Total-Body Irradiation and Bone Marrow Transplantation

Pulmonary tissue is sensitive and often treatment-limiting in patients exposed to total-body irradiation (TBI) in preparation for hematopoietic stem cell transplantation. Many rodent strains, however, exhibit a relatively high resistance to radiation lung damage that often requires extra radiation doses to be delivered locally to the thorax to generate significant levels of pulmonary injury. The present study compared the effects of TBI and bone marrow transplantation (BMT) on two mouse strains that are known to differ in lung radiosensitivity after whole-thorax irradiation, namely the relatively resistant CBA mice and the sensitive C57L mice. Evaluation by survival, microcomputerized tomography (micro-CT), lung tissue weights and histopathology showed that the C57L mice responded with severe lethal radiation pneumonitis at 4 months after 12.5 Gy while CBA mice showed only minimal sublethal damage at this dose. C57L mice receiving 10 Gy TBI also had focal fibrotic lesions in the lungs out to 8 months. The manifestation of both pneumonitis and focal fibrosis in the lungs of C57L mice at relatively low radiation doses points to the merits of using this strain in further studies aimed at exploring and ameliorating the high susceptibility of the lung as encountered in clinical TBI.

Murid herpesvirus‐4 induces chronic inflammation of intrahepatic bile ducts in mice deficient in gamma‐interferon signalling

Infection of gamma interferon receptor defective mice with murid herpesvirus-4 also known as murine gammaherpesvirus-68 results in multi-organ fibrosis. In this paper we characterise the pathological changes occurring in the liver in this model. Standard immunohistochemistry and in situ hybridisation techniques were used to identify the cellular changes and the presence of virus at different times post infection. In liver sections from infected gamma interferon receptor defective mice sampled on day 16 to at least day 120, 79% showed proliferating intrahepatic bile ducts associated with a chronic mononuclear cell inflammation. Only 8% of wild type mice showed similar lesions. Coincident with the inflammatory response bile duct epithelial cells were positive for arginase 1. Around day 50 post infection onwards focal fibrotic lesions appeared in approximately 30% of gamma interferon receptor defective mice resulting in destruction of intrahepatic bile ducts. In contrast to the chronic persisting inflammatory response the presence of virus infected cells were only observed between day 12-20 post-infection. Infection of gamma interferon receptor defective mice with a murine gammaherpesvirus initiates a chronic persisting inflammatory response with a pathological profile similar to the human fibrotic liver disorder Primary Sclerosing Cholangitis.

Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart

In addition to cardiac myocyte hypertrophy, proliferation and increased extracellular matrix production of cardiac fibroblasts occur in response to cardiac overload. This remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy leading to ventricular dysfunction and heart failure. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones produced primarily by the atrium and ventricle, respectively. Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders. ANP and BNP exhibit diuretic, natriuretic, and vasodilatory activities via a guanylyl cyclase-coupled natriuretic peptide receptor subtype (guanylyl cyclase-A or GC-A). Here we report the generation of mice with targeted disruption of BNP (BNP-/- mice). We observed focal fibrotic lesions in ventricles from BNP-/- mice with a remarkable increase in ventricular mRNA expression of ANP, angiotensin converting enzyme (ACE), transforming growth factor (TGF)-beta3, and pro-alpha1(I) collagen [Col alpha1(I)], which are implicated in the generation and progression of ventricular fibrosis. Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP-/- mice. No signs of cardiac hypertrophy and systemic hypertension were noted in BNP-/- mice. In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP-/- mice examined, accompanied by further increase of mRNA expression of TGF-beta3 and Col alpha1(I). We postulate that BNP acts as a cardiocyte-derived antifibrotic factor in the ventricle.

Cardiac fibrosis in mice lacking brain natriuretic peptide.

Cardiac fibrosis, defined as a proliferation of interstitial fibroblasts and biosynthesis of extracellular matrix components in the ventricles of the heart, is a consequence of remodeling processes initiated by pathologic events associated with a variety of cardiovascular disorders, which leads to abnormal myocardial stiffness and, ultimately, ventricular dysfunction. Brain natriuretic peptide (BNP) is a cardiac hormone produced primarily by ventricular myocytes, and its plasma concentrations are markedly elevated in patients with congestive heart failure and acute myocardial infarction. However, its precise functional significance has been undefined. In this paper, we report the generation of mice with targeted disruption of BNP (Nppb(-/-) mice). We observed multifocal fibrotic lesions in the ventricles from Nppb(-/-) mice. No signs of systemic hypertension and ventricular hypertrophy are noted in Nppb(-/-) mice. In response to ventricular pressure overload, focal fibrotic lesions are increased in size and number in Nppb(-/-) mice, whereas no focal fibrotic changes are found in wild-type littermates (Nppb(+/+) mice). This study establishes BNP as a cardiomyocyte-derived antifibrotic factor in vivo and provides evidence for its role as a local regulator of ventricular remodeling.

Development of Fibrosis after Lung Irradiation in Relation to Inflammation and Lung Function in a Mouse Strain Prone to Fibrosis

The development of lung fibrosis after single-dose thoracic irradiation was studied histologically in C57L/J male mice. Lung function was monitored using uptake of carbon monoxide. During the latent period (prior to 15 weeks postirradiation) mice were chosen at random, while during the early phase (15-22 weeks) mice were sacrificed when they developed a functional deficit of at least 50%. Excess mice with a deficit of 50% in the early phase were followed into the late phase and sacrificed at 31 or 40 weeks. Two scoring methods were used to quantify lung damage. Fibrotic lesions and foci of inflammation were counted for the latent period, and the proportion of nonfunctional acini was determined for the early and late phases. After a dose 1 Gy less than the LD50/180, small regions of mild inflammatory infiltration appeared at 6 weeks, and small, focal fibrotic lesions containing numerous macrophages appeared at 8 weeks postirradiation. The number of fibrotic lesions increased steadily during the latent period in a manner that is consistent with conversion of inflammatory lesions to foci of fibrosis. Mice sacrificed upon developing a 50% functional deficit during the early phase had approximately equal proportions of lung affected by fibrosis and inflammation. Those mice which developed a similar respiratory deficit in the early phase and were followed into the late phase usually showed little change in lung function. However, when sacrificed at 31 weeks they had twice as much fibrosis and very little inflammation, suggesting that the inflammatory lesions had become fibrosed. The average number of macrophages per unit area of fibrosis declined during the latent period and changed little during the early and late phases. Lymphocytes and mast cells were also quantified in fibrosed regions.

肥育牛にみられた心内膜線維弾性症の1例

Clinical and pathological examinations were conducted on a 21-month-old fattening ox with endocardial fibroelastosis. Auscultationally, the first and second sounds were of sufficient intensity to be heard and there was also a loud systolic murmur. An Elecrocardiograph indicated prolonged P waves and a QRS complex and increased amplitude of T waves. A phonocardiograph gave indication of crescendo-decrescendo systolic murmur in the vicinity of the bilateral atrio-ventricular valves. Marked hypertrophy of the heart was evident by ultrasonography.The results of autopsy showed marked hypertrophy of the heart and whitish and diffuse lesions of fibrotic thickening on the endocardium of the right atrium, ventricle, and chordae tendineae. Focal fibrotic lesions were also present on the endocardium of the left ventricular outflow tract. Microscopical examination demonstrated proliferation of collagen and elastic fibers in the endocardium of the bilateral atrium, ventricle, and sub-endocardial interstitial tissue. Thickening of arterial walls was also evident.

Dilated cardiomyopathy in Holstein-Friesian cattle

Dilated cardiomyopathy has been observed in Holstein-Friesian cattle maintained in Japan. The incidence was estimated to be about 141/100 000 of slaughtered cattle in central Japan. The 23 cases in our series included two heifers and four steers as well as adult dairy cows. In eight cases, onset was within 4 months after the last parturition, and four cows were still pregnant. Sudden onset of cdcma in the submandibular portion to the brisket was one of the first signs. Common lesions included pronounced subcutaneous edema, congestion of the liver, and dilated heart. Transmural diffuse fibrosis of both ventricles and the ventricular septum was seen in 22 cases. A young dairy cow slaughtered soon after onset showed focal fibrotic lesions, sparsely distributed in all layers of the myocardium. Hypertrophy or swelling of the myocardial fibers with vacuolation was also prominent. Some fibers contained bizarre or multiple nuclei. The only cellular reaction was occasional lymphocytic infiltration in the interstitium. This bovine disease may be a good animal model for the study of dilated cardiomyopathy in man.