Arnold R. Brody's research while affiliated with North Carolina State University and other places
What is this page?
This page lists the scientific contributions of an author, who either does not have a ResearchGate profile, or has not yet added these contributions to their profile.
It was automatically created by ResearchGate to create a record of this author's body of work. We create such pages to advance our goal of creating and maintaining the most comprehensive scientific repository possible. In doing so, we process publicly available (personal) data relating to the author as a member of the scientific community.
If you're a ResearchGate member, you can follow this page to keep up with this author's work.
If you are this author, and you don't want us to display this page anymore, please let us know.
It was automatically created by ResearchGate to create a record of this author's body of work. We create such pages to advance our goal of creating and maintaining the most comprehensive scientific repository possible. In doing so, we process publicly available (personal) data relating to the author as a member of the scientific community.
If you're a ResearchGate member, you can follow this page to keep up with this author's work.
If you are this author, and you don't want us to display this page anymore, please let us know.
Publications (231)
Both cigarette smoke (CS) and asbestos cause lung inflammation and lung cancer, and at high asbestos exposure levels, populations exposed to both of these carcinogens display a synergistic increase in the development of lung cancer. The mechanisms through which these two toxic agents interact to promote lung tumorigenesis are poorly understood. Her...
BACKGROUND AND PURPOSE Inhalation of a β‐adrenoceptor agonist (β‐agonist) is first‐line asthma therapy, used for both prophylaxis against, and acute relief of, bronchoconstriction. However, repeated clinical use of β‐agonists leads to impaired bronchoprotection and, in some cases, adverse patient outcomes. Mechanisms underlying this β2‐adrenoceptor...
Inhalation of a β-adrenoceptor agonist (β-agonist) is first-line asthma therapy, used for both prophylaxis against, and acute relief of, bronchoconstriction. However, repeated clinical use of β-agonists leads to impaired bronchoprotection and, in some cases, adverse patient outcomes. Mechanisms underlying this β(2) -adrenoceptor dysfunction are not...
Side population (SP) assay composed of Hoechst 33342 staining and subsequent flow cytometric analysis has been widely utilized for characterizing putative cancer stem cells (CSCs) in various human malignancies. The present study was designed to evaluate the SP assay as a research tool for mesothelial CSCs. A distinct fraction of SP cells was identi...
Mesenchymal stem cells (MSCs) have been shown to differentiate into a variety of mesenchymal cell types, including fibroblasts, myofibroblasts, osteoblasts, chondroblasts, adipocytes, and myoblasts, as well as epithelial cells. It has been shown that these cells can be recovered from bone marrow as well as umbilical cord blood, and they can be prop...
Mesenchymal stem cells (MSCs) reside within tissues such as bone marrow, cord blood, and dental pulp and can differentiate into other mesenchymal cell types. Differentiated MSCs, called circulating fibrocytes, have been demonstrated in human lungs and migrate to injured lung tissue in experimental models. It is likely that MSCs migrate from the bon...
Carbon nanotubes are shaped like fibres and can stimulate inflammation at the surface of the peritoneum when injected into the abdominal cavity of mice, raising concerns that inhaled nanotubes may cause pleural fibrosis and/or mesothelioma. Here, we show that multiwalled carbon nanotubes reach the subpleura in mice after a single inhalation exposur...
Studies have been carried out previously to determine whether mesenchymal stem cells (MSC) influence the progression of pulmonary fibrosis. Here, we asked whether MSC (derived from mouse bone marrow and human umbilical cord blood) produce factors that mediate lung fibroblast (LF) growth and matrix production. MSC-conditioned media (CM) were found b...
Tumour necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) are peptides with multiple biological activities that influence neoplastic, immunologic and fibroproliferative diseases. There are clear interrelationships and overlap between the actions of TNF-α and TGF-β1 in lung fibrosis; therefore, we postulated that TNF-α may play a s...
Tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(1) (TGF-beta(1)) are peptides with multiple biological activities that influence neoplastic, immunologic and fibroproliferative diseases. There are clear interrelationships and overlap between the actions of TNF-alpha and TGF-beta(1) in lung fibrosis; therefore, we postula...
The alveolar macrophage (AM) is pleomorphic in shape, with complex surface folds and ruffles. Two morphologic types of human AM from nonsmokers were identified in scanning electron microscopic studies of fresh plastic-adherent mono layers: flat cells (55%) and round cells (45%). The assumption of a flat, or spread, cell shape was complete after 30...
The alveolar epithelium contains tight junctions and provides a barrier to passage of potentially injurious substances into the pulmonary interstitium. Alveolar epithelial injury is hypothesized to be an important early event in the pathogenesis of asbestosis. Mechanisms that may contribute to alveolar epithelial cell injury following asbestos expo...
Interstitial lung disease (ILD) afflicts millions of people worldwide. ILD can be caused by a number of agents, including inhaled asbestos, and may ultimately result in respiratory failure and death. Currently, there are no effective treatments for ILD. Transforming growth factor-beta1 (TGF-beta1) is thought to play an important role in the develop...
Abstract Inhalation of asbestos fibers results in progressive interstitial pulmonary fibrosis in the bronchiolar-alveolar regions of humans and experimental animals. The fibrogenic lesions were described previously by morphometry in a rodent model of asbestos-induced pulmonary fibrosis in our laboratory. Our prior studies also showed that incorpora...
The purpose of the workshop was to identify still obscure or novel cellular components of the lung, to determine cell function in lung development and in health that impacts on disease, and to decide promising avenues for future research to extract and phenotype these cells. Since robust technologies are now available to identify, sort, purify, cul...
Our current alveolar paradigm includes three highly specialized cell populations. Alveolar type I cells are flat, elongated cells that presumably enable gas exchange. Alveolar type II cells are small, cuboidal cells with metabolic, secretory, progenitor, and immunologic functions. Alveolar fibroblasts secrete extracellular matrix proteins that supp...
Tumor necrosis factor-alpha (TNFalpha) and transforming growth factor-beta(1) (TGFbeta(1)) are potent peptide growth factors that are likely to play important roles in the development of interstitial pulmonary fibrosis (IPF). Previously we showed that TNFalpha and TGFbeta(1) are up-regulated in macrophages, epithelial and mesenchymal cells early af...
The genes that mediate fibroproliferative lung disease remain to be defined. Prior studies from our laboratory showed by in situ hybridization and immunohistochemistry that the genes coding for tumour necrosis factor alpha, transforming growth factor beta, the platelet-derived growth factor A and B isoforms, and alpha-1 pro-collagen are expressed i...
Bone marrow-derived cells have been shown to engraft during lung fibrosis. However, it is not known if similar cells engraft consequent to inhalation of asbestos fibers that cause pulmonary fibrosis, or if the cells proliferate and differentiate at sites of injury.
We examined whether bone marrow-derived cells participate in the pulmonary fibrosis...
Specialised surface differentiations exist in brush cells, alternatively called tuft cells or caveolated cells. Brush cells
belong to a cell population that is widely distributed in the epithelial organs of the gastrointestinal and respiratory tracts,
such as the stomach, the small and large intestine, the bile duct, the gallbladder and pancreatic...
Increased expression of transforming growth factor (TGF)-beta(1) and tumor necrosis factor (TNF)-alpha are thought to play important roles in the development of pulmonary fibrosis. We recently reported that TNF-alpha upregulates TGF-beta(1) expression in primary mouse lung fibroblasts (MLFs), a key cell population in fibrogenesis. In the present st...
This chapter discusses the roles and importance of selected mediators in chronic lung injury and fibroproliferation. A multiplicity of intracellular and extracellular mediators, factors, and signaling pathways is relevant for chronic lung injury, including many that are also involved in acute lung injury. The pathophysiology and clinical importance...
Pleural fibrosis resembles fibrosis in other tissues and can be defined as an excessive deposition of matrix components that results in the destruction of normal pleural tissue architecture and compromised function. Pleural fibrosis may be the consequence of an organised haemorrhagic effusion, tuberculous effusion, empyema or asbestos-related pleur...
Akt is a signal transduction protein that plays a central role in inhibiting apoptosis in a variety of cell types including human cancer cells. In cell lines derived from human non-small cell lung cancers (NSCLCs), Akt has been shown to confer chemoresistance by inhibition of apoptosis in response to different chemotherapeutic agents including plat...
Transforming growth factor-beta1 (TGF-beta1) is a potent peptide that inhibits epithelial and mesenchymal cell proliferation and stimulates the synthesis of extracellular matrix components. This cytokine is produced in a biologically latent complex bound to a latent-associated peptide (LAP), and it is the disassociation of this complex that regulat...
The gene encoding the p53 tumor suppressor protein is commonly mutated in many human cancers, including lung cancer,¹but p53 mutations are relatively rare in murine lung tumors induced by carcinogen exposures.²To model the pathogenesis of human lung cancers in mice, we disrupted wild-type p53 activities by transgenically expressing a dominant-negat...
Platelet-derived growth factor (PDGF) isoforms and PDGF receptor-alpha are upregulated in fibroproliferative lesions in response to asbestos exposure. To examine the functional role of PDGF in asbestos-induced lung disease, we have evaluated the impact of PDGF-B overexpression in the lung on the development of pulmonary fibrosis induced by asbestos...
Pulmonary fibrosis (PF) is caused by a number of inhaled agents, as well as by some drugs and toxic particles. The elaboration of certain peptide growth factors is thought to be key to the development of this disease process. In addition, genetic susceptibility plays a role in the development of PF. For instance, we have previously shown that the 1...
The chemotherapeutic drug bleomycin causes DNA damage and apoptosis in the lungs of mice within hours of endotracheal instillation followed by inflammation and fibrosis weeks later. The p53 tumor suppressor protein mediates cellular responses to DNA damage, including induction of apoptosis, but the effects of p53 activation in the various cell type...
Investigators have shown that interstitial pulmonary fibrosis (IPF) can be induced in rats by overexpressing transforming growth factor beta1 (TGF-beta1) through a replication-deficient recombinant adenovirus vector instilled into the lungs (Sime et al. 1997). We have shown that this vector induces IPF in fibrogenic-resistant tumour necrosis factor...
Lung fibroblasts are activated to proliferate and produce connective tissue during the development of lung fibrosis. The 129 mouse strain does not develop asbestos-induced fibrogenesis, whereas several other inbred strains rapidly respond to inhaled fibers. Thus, in the experiments presented here, we have compared the responses of primary lung fibr...
The bronchiolar-alveolar epithelium (BAE) is a primary target site for inhaled agents that cause lung injury. These cells, consequently, release a broad range of mediators that influence other cell populations, including interstitial lung fibroblasts that are central to the development of interstitial pulmonary fibrosis (IPF). A number of peptide g...
In an alternative approach to assess p53 function in the lung epithelium after exposure to asbestos, mice that overexpress wild-type p53 from the surfactant protein C promoter, SPC-wtp53 transgenic mice, and nontransgenic littermates were exposed to an aerosol of asbestos fibers on 3 consecutive days for 5 h each day. In previous experiments, this...
Tumor necrosis factor-alpha receptor knockout (TNF-alphaRKO) mice have homozygous deletions of the genes that code for both the 55- and 75-kD receptors. The mice are protected from the fibrogenic effects of bleomycin, silica, and inhaled asbestos. The asbestos-exposed animals exhibit reduced expression of other peptide growth factors such as transf...
Inhalation of numerous fibrogenic agents causes interstitial pulmonary fibrosis (IPF) in humans and in a number of animal models. Several of these models provide evidence that certain peptide growth factors (GF) are playing a role in the disease process. Transforming growth factor beta 1 (TGF-beta1) is a potent inducer of extracellular matrix produ...
Murine exposure to silica is associated with enhanced tumor necrosis factor alpha (TNF-alpha) expression and matrix deposition. The regulation of TNF is mediated through TNF receptor (TNFR) activation of transcription factors. In the present work we have studied the importance of the individual TNFR in silica-induced lung inflammation and matrix de...
Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular m...
It would be impossible to completely review this broad topic in the space and time allowed. Just as we must make choices when focusing on a research topic, this brief overview of particles and fibrosis deals with a small corner of our current thinking on the molecular mechanisms through which inhaled particles mediate fibroproliferative lung diseas...
Herein we present new data showing that two strains of mice are protected from the fibrogenic effects of inhaled asbestos fibers. One is an inbred, the 129 strain, and the second an F2 hybrid from a C57BL/6 (C57) and 129 cross (C57-129) that has had both the 55- and 75-kd receptors for TNF-α knocked out (C57-129KO). When these mice were exposed to...
Because of its expression pattern and its potent effects on mesenchymal cells, platelet-derived growth factor (PDGF) has been implicated as an important factor in epithelial-mesenchymal cell interactions during normal lung development and in the pathogenesis of fibrotic lung disease. To further explore the role of PDGF in these processes, we have d...
We have investigated a potential role for tumor necrosis factor (TNF)-alpha and its two receptors (p55 and p75) in lung injury. We used several varieties of mice exposed endotracheally to two fibrogenic agents, silica (0.2 g/kg) and bleomycin (4 U/kg). The lungs were analyzed at 14 and 28 d after exposure to bleomycin or silica, respectively, for T...
Tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β mRNA and protein expression and the degree of fibroproliferative response to inhaled asbestos fibers are clearly reduced in the 129 inbred mouse strain as compared with typical fibrogenesis observed in the C57BL/6 inbred strain. The C57BL/6 mice showed prominent lesions at bronchi...
We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-alpha knocked out (TNF-alphaRKO) fail to develop fibroproliferative lesions after asbestos exposure. There is good evidence that TNF-alpha plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we pr...
Apoptosis is considered to be a protective mechanism that limits lung injury. However, apoptosis might contribute to the inflammatory burden present in the injured lung. The exposure of mice to bleomycin (BLM) is a well-established model for the study of lung injury. BLM exposure induces DNA damage and enhances tumor necrosis factor (TNF)-α express...
A non-radioactive method of in situ hybridization was used to localize transforming growth factor-alpha mRNA in epithelial cells of collecting ducts and tubules in rat kidney tissue sections. The intensity and specificity of staining were assessed under a variety of tissue preparation conditions, including a direct comparison of paraffin against fr...
Bleomycin (BLM) induction of lung fibrosis in mice is an established model to study the mechanism of pulmonary fibrosis. Cytokine secretion has been implicated as a fundamental component of the lung fibrotic process observed in response to BLM. Among the cytokines implicated in lung fibrosis, Tumor necrosis factor (TNF) alpha has been considered to...
Connective tissue growth factor (CTGF) is a newly described 38-kDa peptide mitogen for fibroblasts and a promoter of connective tissue deposition in the skin. The CTGF gene promotor contains a transforming growth factor-beta1 (TGF-beta1) response element. Because TGF-beta1 expression is upregulated in several models of fibroproliferative lung disea...
Platelet-derived growth factor-AA (PDGF-AA) and its matching alpha receptor (PDGF-R alpha) are upregulated in rat lung fibroblasts (RLFs) after exposure to chrysotile asbestos fibers in vitro, which results in asbestos-induced RLF proliferation. We now report our in vivo observations, which show an increase in the expression of PDGF-R alpha mRNA, b...
Corticosteroids (CSs) are commonly used for anti-inflammatory therapy in asthma and in interstitial lung diseases. In attempting to understand the mechanisms through which CSs control cell proliferation, we have carried out experiments to test the effects of dexamethasone (Dex) on the growth of lung fibroblasts. Using mouse 3T3 fibroblasts as well...
Inhalation of fibrogenic particles causes injury to the bronchiolar-alveolar epithelium. Consequently, there is a rapid proliferative response as the epithelium recovers and interstitial mesenchymal cells divide and produce connective tissue. In our model of brief (5-hr) exposure to chrysotile asbestos (approximately 1000 fibers/cc) in rats and mic...
The development of interstitial pulmonary fibrosis is associated with a variety of inflammatory mediators, including peptide growth factors and cytokines. In the work presented here, we have asked whether or not platelet-derived growth factor (PDGF)-A and -B genes and proteins are expressed in anatomic and temporal patterns consistent with this fac...
Occupational lung disease can take many forms, including obstructive airway disease, asthma, and restrictive parenchymal fibrosis. It would not be useful to attempt an all-encompassing review of such a broad topic, even if one were restricted to the most recent literature. Thus, I have chosen a small corner of one disease process that relates to wo...
Humans and rodents exposed to an aerosol of asbestos fibers develop lung injury that can lead to a fibroproliferative response culminating in excessive scarring and impaired lung function. To define the early events that precede asbestos-induced fibrotic lung disease, rats were exposed to an aerosol of chrysotile asbestos fibers for 5 h. At various...
Mouse lung fibroblasts (MLFs) were isolated from the lungs of patch mice, which are heterozygous for expression of the PDGF-Rα, and their wild type (WT) littermates. PDGF-Rα expression in patch and WT MLFs was compared using a radioreceptor assay. Scatchard analysis revealed that patch MLFs express only 58±7% (P < 0.05, n=3) as many of the PDGF-Rα...
In three separate experiments, we have demonstrated a clear difference in the degree of fibroproliferative lung lesions in two inbred mouse strains (C57B1/6 and 129) commonly used in making knockouts. Animals from each strain were exposed to asbestos fibers and sacrificed at 0 hr. 48 hrs, 1 wk. 2 wks and 4 wks post-exposure. Blinded, semi-quantitat...
Previously, this laboratory developed a model of asbestos-induced pulmonary fibrogenesis in rats and mice after a brief (1 to 3-h) inhalation exposure. However, typical human environmental exposures would be repeated, although at lower concentrations than those used in our animal model. Here we have extended this model to encompass repeated exposur...
It has become apparent that the numerous growth factors and cytokines are produced during the development of fibroproliferative lung disease. Investigators must sort out which combinations of these factors are playing mechanistic roles in the disease process. Here we demonstrate that transforming growth factor (TGF)-alpha, a potent epithelial and m...
Previous attempts to culture mouse alveolar type II (ATII) cells have been hampered by limited purity and cell recovery. We have now obtained culturable ATII cells from female C57BL/6 mice at a purity of 92% +/- 3 (mean +/- SD; n = 20), with viabilities of 96% +/- 2 and total yields of 5.1 +/- 0.7 X 10(6) cells per mouse. Crude lung cell suspension...
Platelet-derived growth factor (PDGF) is a potent mediator of fibroblast proliferation and chemotaxis. We have studied here the cytokine interferon-γ (IFN-γ) which is known to prime macrophages for increased PDGF production. Thus, we postulated that IFN-γ would act as a positive regulator of PDGF-BB secretion by rat alveolar macrophages, and in add...
Inhaled asbestos fibers initiate the events that generate a fibrotic scar at the sites of fiber deposition in the lung. Our previous work demonstrated that the p53 tumor suppressor protein and the proliferating cell nuclear antigen (PCNA), a DNA replication and repair protein, are co-expressed in a rat model of asbestos-induced lung injury and repa...
We have been using a model of asbestos-induced lung fibrosis in rats and mice to determine which of the many growth factor genes and their protein products are playing a role in mediating the disease process. Recently we learned that the gene coding for transforming growth factor alpha (TGFa) and its mitogenic protein were expressed almost exclusiv...
We have compared the fibrotic response of two strains of mice commonly used in making transgenics. Twelve mice of each strain, C57BL/6 and 129, were exposed to asbestos (-1000 fibers/cc) for 5 hours with 12 unexposed mice used as controls. In a blinded semiquantitative (0-3+) scoring of H & E stained lung sections, clear differences in the fibrotic...
Numerous cytokines and growth factors signal the normal processes of tissue maintenance and remodeling in the lung, yet the aberrant expression of these peptide mediators is involved in a variety of pulmonary diseases. Furthermore, several different binding proteins function in controlling the extracellular levels of many of these cytokines in the...
Rats were exposed, by inhalation, to target airborne fibre concentrations of 1000 f/ml (PCOM fibres by WHO criteria) of a long amosite asbestos sample and a vitreous fibre sample; the target was closely attained for both fibre samples. The size distributions of the two fibre samples was closely similar. Rats were placed in the chambers for 7 hours...
We have investigated the mitogenic and chemotactic role of platelet-derived growth factor (PDGF) in pulmonary fibrogenesis induced by chrysotile asbestos. Since fibroblasts phagocytize asbestos in the lung interstitium, we have sought to learn whether the fibers alter the production of PDGF-like molecules by rat lung fibroblasts or induce mitogenes...
Platelet-derived growth factor (PDGF) isoforms are chemoattractants and mitogens for cells of mesenchymal origin that could be important mediators of pulmonary fibrogenesis. We have previously reported that particle-activated alveolar macrophages secrete homologues of PDGF that are composed of all three PDGF isoforms (PDGF-AA, -AB, and -BB). This m...
We have been studying early fibroproliferative events in the lungs of rodents exposed to aerosols of asbestos fibers. In the experiments presented here, incorporation of bromodeoxyuridine (BrdU) in the bronchiolar/alveolar (B/A) regions of the lungs in mice was assessed following two consecutive exposures to chrysotile asbestos. Six to 8-week-old m...
The distribution of inhaled mineral fibers in the lung determines the site and severity of disease caused by the fibers. Some of our recent work has described the fate of inhaled asbestos fibers in rodents. After a brief inhalation exposure, asbestos fibers are deposited primarily at the first alveolar duct bifurcations, and fibrotic lesions are in...
PDGF isoforms have been postulated to serve as mediators of fibroblast proliferation and chemotaxis during lung fibrogenesis induced by asbestos inhalation. We have studied the interaction of chrysotile asbestos fibers with rat lung fibroblasts (RLF) in vitro and the consequent changes in PDGF receptor mRNA expression, PDGF binding, and mitogenic a...
Lung fibrosis has been postulated to be mediated by the production of macrophage-derived growth factors that are both mitogenic and chemotactic for fibroblasts. In vitro studies from our laboratory demonstrated that alveolar and interstitial macrophages treated with iron and asbestos release platelet-derived growth factor (PDGF) and transforming gr...
This review attempts to deal with two major questions concerning asbestos-induced lung disease: How does inhaled asbestos cause cell proliferation and fibrosis? and Will there continue to be risk from exposure to asbestos in schools and public buildings? The first is a scientific question that has spawned many interesting new experiments over the p...