Early signs of lung fibrosis after in vitro treatment of rat lung slices with CdCl2 and TGF-?1

Kasper, Michael; Seidel, D.; Knels, Lilla; Morishima, Nobuhiro; Neisser, Anja; Bramke, Silvia; Koslowski, Roland

doi:10.1007/s00418-003-0612-6

Cited by 61 publications

(48 citation statements)

References 27 publications

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“…Indeed, there is substantial evidence from other animal models that changes occur in adventitial cells (including extracellular matrix protein production) as an early response to perturbations that cause PH, including hypoxia, 54 monocrotaline exposure, 55 and even with ex vivo exposure to cadmium and transforming growth factor-␤. 56 Furthermore, the type of perivascular fibrosis we report here is also seen in some human patients with chronic bronchiolar inflammation. 57 Therefore, in our report the sustained PH that persists after clearance of both the Pneumocystis infection and most of the inflammatory cells may be attributable to quantitative rather than qualitative differences of the disease process.…”

Section: Discussionsupporting

confidence: 67%

Pulmonary Hypertension Can Be a Sequela of Prior Pneumocystis Pneumonia

Swain

Han

Harmsen

et al. 2007

The American Journal of Pathology

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Improved treatment regimens have reduced fatalities from opportunistic diseases, such as Pneumocystis pneumonia, in AIDS patients. However, serious chronic conditions, including pulmonary hypertension (PH), are increasing in this group. We report here that when CD4 T cells in Pneumocystis-infected mice are temporally depleted and then allowed to return, the extended inflammation results in PH that persists after Pneumocystis is eliminated. Using this model of PH, we have found that i) the onset of PH is correlated with the return of CD4 T cells, but PH persists after CD4 levels diminish; ii) vascular remodeling accompanies PH, but whereas temporary medial hypertrophy is evident with transient PH in immunocompetent mice, persistent PH is associated with perivascular fibrosis; iii) elevated levels of the fibrotic mediator FIZZ1 are found in bronchoalveolar lavage fluid of mice with persistent PH; and iv) although Th2-related mechanisms may be involved in PH etiology, PH still occurs in interleukin-4 receptordeficient mice under these conditions. Overall, the data presented here demonstrate that the immune response to an infectious disease pathogen, such as Pneumocystis, can, when perturbed and prolonged, lead to later development of a serious chronic condition such as PH.

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Section: Discussionsupporting

confidence: 67%

Pulmonary Hypertension Can Be a Sequela of Prior Pneumocystis Pneumonia

Swain

Han

Harmsen

et al. 2007

The American Journal of Pathology

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“…30 Sections of lung were deparaffinized with xylene and hydrated with an ethanol series, washed in tap water, and stained with a Sirius Red/fast green solution for 30 minutes at room temperature. They were washed again and dehydrated in an ethanol series and xylene.…”

Section: Histologymentioning

confidence: 99%

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

Englert

Hanford

Kaminski

et al. 2008

The American Journal of Pathology

209

220

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Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease associated with a dismal prognosis. There are currently no effective therapies for IPF, thus the identification of novel therapeutic targets is greatly needed. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation has been linked to various pathologies. In healthy adult animals, RAGE is expressed at the highest levels in the lung compared to other tissues. To investigate the hypothesis that RAGE is involved in IPF pathogenesis, we have examined its expression in two mouse models of pulmonary fibrosis and in human tissue from IPF patients. In each instance we observed a depletion of membrane RAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, immunohistochemical and hydroxyproline quantification studies on aged RAGEnull mice indicate that these mice spontaneously develop pulmonary fibrosis-like alterations. Furthermore, when subjected to a model of pulmonary fibrosis, RAGE-null mice developed more severe fibrosis, as measured by hydroxyproline assay and histological scoring, than wild-type controls. Combined with data from other studies on mouse models of pulmonary fibrosis and human IPF tissues indicate that loss of RAGE contributes to IPF pathogenesis. Idiopathic pulmonary fibrosis (IPF) is a debilitating disease with a dismal prognosis. Mean survival time after biopsy-confirmed diagnosis is 3 to 5 years.1,2 Traditional therapy involves the use of corticosteroids as nonspecific anti-inflammatory agents. This treatment produces an objective response in only 10 to 20% of patients and has a minimal effect on the fatal course of IPF.2-4 Thus, the need for new therapeutic modalities is evident.The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin super family of cell surface receptors. 5 In most healthy adult animal tissues, RAGE is expressed at low to undetectable levels.6,7 Activation of membrane-bound RAGE (mRAGE) by its ligands (including advanced glycation end products, HMGB1/amphoterin, S100/calgranulins, and amyloid-␤ peptide) often leads to proinflammatory signaling as well as up-regulation of RAGE itself.8 This signaling by mRAGE is believed to play an important role in disease progression for several nonpulmonary diseases, including various diabetic complications, chronic inflammation, and Alzheimer's disease, among others. 9,10 In contrast to other healthy adult tissues, RAGE mRNA and sRAGE protein are highly expressed in normal adult lungs. 6,7,11 Most recently it has been suggested that RAGE is a marker of type I alveolar epithelial cells 12 and type II alveolar epithelial cell transdifferentiation, a component of pulmonary re-epithelialization and repair.

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“…In the present study PCLS from sheep were viable for at least three days, not different from the viability of human PCLS [24], making it possible to study the effects of cytokines, growth factors and maybe even remodeling processes [35,36]. In addition, recent work by Behrsing and colleagues [37] has demonstrated that the process of slicing itself elicits a massive cytokine response, confounding early results of cytokine measurements in response to PCLS challenge.…”

Section: Discussionmentioning

confidence: 67%

Comparison Of Airway Responses In Sheep Of Different Age In Precision-cut Lung Slices (PCLS)

Schlepütz

Dassow

Kramer

et al. 2010

C65. Mechanics of the Lung Periphery in Asthma: New Findings

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Background: Animal models should display important characteristics of the human disease. Sheep have been considered particularly useful to study allergic airway responses to common natural antigens causing human asthma. A rationale of this study was to establish a model of ovine precision-cut lung slices (PCLS) for the in vitro measurement of airway responses in newborn and adult animals. We hypothesized that differences in airway reactivity in sheep are present at different ages.

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Early signs of lung fibrosis after in vitro treatment of rat lung slices with CdCl2 and TGF-?1

Cited by 61 publications

References 27 publications

Pulmonary Hypertension Can Be a Sequela of Prior Pneumocystis Pneumonia

Pulmonary Hypertension Can Be a Sequela of Prior Pneumocystis Pneumonia

A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

Comparison Of Airway Responses In Sheep Of Different Age In Precision-cut Lung Slices (PCLS)

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