News about Health (Part 5)

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: UIP changes

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: UIP changesCats with IPF acquire lung histopathology similar to human IPF. Previous to the 2000 statement designating UIP as the pathologic manifestation of IPF, acute interstitial pneumonia, desquamative interstitial pneumonia, and NSIP were also considered variations of IPF. These other pulmonary diseases lack the temporal heterogeneity and evidence of ongoing fibrogenesis of IPF. Complicating this classification system is the finding of Flaherty et al, who found considerable variation between lobes of individual patients with IPF; many of the patients had histologic features consistent with fibrotic NSIP in lobes away from the UIP changes. We are unable at this time to discuss the uniformity of changes between lobes in individual cats because the tissues examined represent material collected from individual lobes, prior to knowledge of the nature of the disease process and the potential for interlobar variability. Examination of entire lung fields from affected cats, with careful sampling of a variety of lobes, will be important to address this question. this

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Human IPF

This study describes spontaneous feline IPF, a newly identified chronic lung disease of domestic cats that shares critical features with human IPF. The important gross pathology, histopa-thology, cell differentiation markers, and ultrastruc-tural features are compared to the well-described features of the disease in humans. IPF in humans is a chronic respiratory disease whose pathology is characterized by temporally heterogeneous, persistent, progressive fibrosis of the lung, usually without significant inflammation. The characteristic morphology consists of patchy remodeling in the lungs leading to honeycomb lung late in the disease, with the characteristic histopathology. This histopathol-ogy shows evidence of temporal heterogeneity with fibrosis, fibroblast foci, and evidence of honeycombing in the parenchyma. Each of these features is found in spontaneous feline IPF. Additionally, ultra-structural features of the type II pneumocytes in feline IPF share morphologic features with the type II cells in a familial form of human UIP, suggesting that the disease in cats may be due to an abnormality in the type II cell. Genetic analysis of surfactant protein genes in affected and normal cats is currently underway, providing hope that the domestic cat may be developed as a new model of IPF. fml ophthalmic drops

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Discussion

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: DiscussionUltrastructure: In the toluidine blue-stained, plastic-embedded lung prepared for electron microscopy, the interstitium of the pulmonary parenchyma was markedly thickened with abundant collagen. In the areas of type II pneumocyte hyperplasia and differentiation, the individual pneumocytes contained many cytoplasmic, variably sized dark inclusions; similar bodies were not seen in normal feline lung (Fig 5, top left, A, and top right, B). By ultrastructure, the type II pneumocytes of normal cats are as described for other species, with surface microvilli and lamellar bodies with stacks of phospholipid membranes (Fig 5, middle left, C). The type II pneumocytes in the IPF cat lung were markedly enlarged (Fig 5, middle right, D), with numerous large condensed lamellar body-like structures (Fig 5, bottom left, E, and bottom right, F). These cells were often free within the lumen of the airspace. Abnormal lamellar bodies were seen within alveolar macrophages as well as occasionally free within the interstitium of the fibrotic lungs. Similar type II pneumocytes were found distant from the foci of remodeling, in the more normal lung parenchyma (data not shown). fully

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Lung

Fibroblast foci, small foci of ongoing mesenchymal cell proliferation with fibroblasts/myofibroblasts and collagen, similar to the foci seen in UIP of humans were observed at the periphery of the honeycomb lung (Fig 3, top left, A [human], and top right, B [feline]). As with human IPF, the epithelial cells overlying the fibroblast foci in feline IPF were often attenuated or cuboidal type II pneumocytes (Fig 3, top left, A [human], and top right, B [feline]).

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Necropsy Findings

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Necropsy FindingsGrossly, the distribution of lesions involved large regions of the lungs. The pleural surface of the lungs was often irregular and cobblestoned in appearance (Fig 1, top, A). The areas of fibrosis and remodeling formed plaque-like depositions that were discrete from the more normal parenchyma, and extended from the subpleural regions to deep within the organ (Fig 1, middle, B). Grossly discernable honeycombing of the lung was uncommon in the cats, but was a prominent feature in a single cat (Fig 1, bottom, C).
A summary of the relative abundance of the four predominant histologic changes in feline IPF, along with the presence or absence of pulmonary neoplasia, is found in Table 2. Histologically, the disease process in cats, as in human IPF, is multifocal, with relatively normal parenchyma interspersed with the affected tissue. The remodeled lung often was most prominent subpleurally (Fig 2, top left, A, and top right, B). The primary histologic changes in cats, as with humans, included interstitial fibrosis with fibroblast/myofibroblast foci, metaplasia of the alveolar epithelium (honeycomb lung), and interstitial smooth-muscle metaplasia/hyperplasia. Interstitial inflammation was variable but usually not prominent (Table 2). In the most severely affected regions of the lungs, there was extension of the histologic alterations into the deep parenchyma without distinction between subpleural and deeper microenvironments (Fig 2, top left, A, and top right, B). acular medication
Honeycombing was present in all cats, and in these areas the epithelium was composed of low-to-tall columnar cells that often formed well-differentiated mucous cells (Fig 2, middle left, C [human], and middle right, D [feline]); mucous cell metaplasia was the predominant phenotype, being present in 69% of the lung samples analyzed (Fig 2, bottom left, E [human], and bottom right, F [feline]). In the cats without mucous cell metaplasia, the lining cells were well-differentiated type II pneumocytes or columnar cells of unknown phenotype; small foci of squamous metaplasia were less commonly a feature of the epithelium. AB-PAS staining of the lung revealed numerous turquoise interstitial mast cells in the fibrotic and honeycomb lung (Fig 2, bottom right, F). The identity of the mast cells was confirmed using immunohistochemistry against mast cell tryptase (inset, Fig 2, bottom right, F).

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Immunohistochemistry

Electron Microscopy:
Tissues from three affected cats were prepared for electron microscopy. The samples were rinsed in 0.1 mol/L phosphate buffer and placed in osmium tetroxide (Electron Microscopy Sciences; Fort Washington, PA) for 3 h. The tissues were then rerinsed in 0.1M phosphate buffer, followed by three 10-min rinses in 30% ethanol. The tissues were transferred into 2% uranyl acetate (Electron Microscopy Sciences) for 1 h, rinsed in 30% ethanol, and dehydrated in a graded series of ethanol. The tissues were placed in propylene oxide, before being embedded in DMP-30 and araldite 501 (Electron Microscopy Sciences); 1 |j,m sections were cut on a LKB ultramicrotome (LKB; Bromma, Sweden), and stained with toluidine blue. Tissues of interest were sectioned at 600 angstroms, stained with uranyl acetate and lead citrate (Electron Microscopy Sciences), and examined on a Phillips 301 electron microscope (Phillips; Atlanta, GA).

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Materials and Methods

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: Materials and MethodsWe report herein a novel spontaneous chronic, progressive respiratory disease in domestic cats with the morphologic features of UIP; these features include the temporal heterogeneity, persistent, progressive proliferation of myofibroblasts/fibroblasts, and an association between IPF and the development of primary pulmonary neoplasia. The light microscopic and ultrastructure characteristics of the type II pneumocytes in spontaneous IPF of cats is similar to a familial form of IPF in humans, suggesting that the disease in cats may be genetically based, and providing an opportunity to develop the cat as a model to study the human disease. Based on these finding we conclude the following: (1) spontaneous chronic respiratory disease with both the clinical and pathology findings consistent with UIP/ IPF occurs in the domestic cat; (2) as with the human disease, hyperplastic type II pneumocytes and myofibroblasts are cellular constituents in feline IPF; (3) the changes in type II pneumocyte ultrastructure in feline IPF are similar to a familial form of human IPF associated with a mutation in the surfactant protein C gene; (4) the altered type II cell ultrastructure suggests spontaneous feline IPF is primarily a defect in the type II pneumocyte; and (5) understanding the cause(s) and pathogenesis of IPF in the cat holds promise for advancing our understanding of the disease in humans.

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis: IPF

Animal models currently used to study IPF do not appropriately mimic the morphologic changes of IPF. As stated in the National Heart, Lung, and Blood Institute workshop summary,2 persistent progressive fibrosis with evidence of temporal heterogeneity is a hallmark of IPF; these features are lacking in the contemporary models of lung fibrosis. Currently, the primary model for the study of IPF is the bleomycin-treated rodent; however, neither the acute nor chronic pulmonary changes resemble UIP. Administration of bleomycin to mice, rats, and hamsters results in pulmonary inflammation and fibrogenesis. Neither the acute or chronic morphology of the lungs of bleomycin-treated rats resembles the changes of IPF. Indeed, there is evidence of spontaneous resolution of the lung injury 4 months after bleomycin treatment, a phenomenon that is not seen in IPF.

Identification of Spontaneous Feline Idiopathic Pulmonary Fibrosis

Identification of Spontaneous Feline Idiopathic Pulmonary FibrosisIdiopathic pulmonary fibrosis (IPF), also known as cryptogenic fibrosing alveolitis, is a poorly understood respiratory disease of humans. Affecting approximately 11 male and 8 female patients, respectively, per 100,000 individuals per year, it is one of the more prevalent interstitial lung diseases. Confounding these many cases is the lack of efficacy of most therapeutics for the disease; this lack of therapeutic options is associated with a 5-year mortality between 50% and 70%. The indolent nature of the disease, with the high mortality, unknown cause(s), and poorly understood pathogenesis makes the identification of appropriate animal models extremely important and challenging. The National Heart, Lung, and Blood Institute of the National Institutes of Health convened a workshop to identify critical future research areas directed toward a better understanding of IPF. Identification/development of an animal model of IPF was deemed critical toward any future progress in filling gaps in understanding of the disease and the testing of future therapeutic modalities. Unfortunately, there is not currently an animal model that recapitulates the progression of the disease, nor develops remodeling within the lungs typical of IPF.

Chemoprevention of Lung Cancer in Transgenic Mice: Use of Transgenic Mouse Model in Chemoprevention Studies

Chemoprevention of Lung Cancer in Transgenic Mice: Use of Transgenic Mouse Model in Chemoprevention StudiesWe examined the effects of two potential agents on the development of adenomas/adenocarcinomas in these mice. The two classes of agents examined were budes-onide’ and the FTI inhibitor L778,123. The former is a glucocorticoid that presumably interacts with the glucocorticoid receptor, and has been shown to be a profoundly effective agent in the A/J mouse model. L778,123 inhibits the farnesyltransferase enzyme that transfers farnesyl onto proteins and allows their transport to and activation in the cell membrane. FTI inhibitors were initially produced because they should block the farnesylation of the mutant Ras oncogenes (H-ras, N-ras, and K-ras). Although they effectively block H-ras and N-ras farnesylation and activation, they do not block farnesylation of K-ras due apparently to the high affinity of this protein for the farnesyltransferase enzyme. We examined the abilities of these agents to inhibit tumor formation either in a prevention setting in which budes-onide was administered beginning prior to benzo(a)pyrene and throughout the study or in a delayed experiment, which we feel may be closer to that achieved in former or current smokers.

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