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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 times after exposure, the lungs of the asbestos-exposed animals were evaluated immunohistochemically for expression of the p53 tumor suppressor protein, a growth regulatory protein. p53 became detectable by immunostaining at the predicted sites of fiber deposition (the bronchiolar-alveolar duct bifurcations) by 24 h after exposure. The number of cells positive for p53 immunostaining increased to a maximal level at 8 days after exposure, decreased by 14 days and returned to a low basal level at the 30-day time point. Control groups of rats that were unexposed or exposed to an aerosol of iron beads were negative for p53 immunostaining throughout the 30-day assessment period. Simultaneous detection of the proliferating cell nuclear antigen (PCNA) at the sites of fiber deposition in the asbestos-exposed animals agrees with our previous finding that p53 binds and regulates the PCNA promoter.
Am J Respir Cell Mol Biol 1997 Apr
PMID:Inhaled asbestos fibers induce p53 expression in the rat lung. 911 60

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 factor playing a role in the disease process. Using an established rat model of asbestos-induced fibroproliferative lung disease, we demonstrate elevated levels of PDGF-A and -B mRNAs in total lung RNA immediately after a single 5-h exposure to approximately 1,000 fibers/ml of chrysotile asbestos. In situ hybridization revealed the PDGF-A and -B in RNAs primarily in macrophages and bronchiolar-alveolar epithelial cells at sites of initial fiber deposition and lung injury. There was clear evidence of PDGF-A and -B mRNAs in interstitial cells as well. The pattern of in situ hybridization was entirely consistent with the appearance (established by immunohistochemistry) of PDGF-A and -B proteins by 24 h post-exposure in the same cell types. Both mRNAs and proteins remained detectable at the fiber deposition sites for almost 2 wk post-exposures. These findings are consistent with our previous studies showing increased mesenchymal cell proliferation and fibroproliferative lesions that progress at the sites where PDGF-A and -B are expressed. Although it is clear that multiple growth factors are produced simultaneously at sites of initial injury, we suggest that the PDGF isoforms could be playing a central role in the disease process based upon their potent mitogenic effects upon mesenchymal cells.
Am J Respir Cell Mol Biol 1997 Aug
PMID:Rapid activation of PDGF-A and -B expression at sites of lung injury in asbestos-exposed rats. 927 Dec 99

Bombesin-like peptides (BLPs) are important regulators of lung development and may also act as autocrine growth factors in lung tumors. We have previously demonstrated expression of mRNA for the three BLP receptor subtypes (neuromedin B [NMB]) receptor, gastrin-releasing peptide [GRP] receptor, and bombesin receptor subtype 3 [BRS-3]) in human non-small cell lung carcinoma (NSCLC) cell lines and bronchial biopsies using the reverse transcription-polymerase chain reaction (RT-PCR; DeMichele, et al. Am. J. Respir. Cell Mol. Biol. 1994; 11:66-74). We have also previously found that growth responses to BLPs could be elicited in some, but not all, cultures of human bronchial epithelial (HBE) cells (Siegfried, et al. Anat. Rec. 1993; 236:241-247). In this report, we utilized RT-PCR to demonstrate mRNA expression of BLP receptor subtypes in cultured HBE cells and also assessed the response of these cultures to BLPs in proliferation assays. The pattern of mRNA expression was correlated with proliferative response, and the results were also analyzed in relation to smoking history and pulmonary function of the subjects studied. Our results suggest that expression of mRNA for the GRP receptor is associated with a long smoking history (> 25 pack-years [PY], p = 0.02). This association was related to past tobacco exposure, regardless of whether the subjects were still active smokers at the time of tissue procurement. Responsiveness to GRP and NMB in proliferation assays was also found only in those HBE cultures with expression of mRNA for at least one of the known receptors for BLPs, and there was a significant association between expression of mRNA for the GRP receptor and proliferative response to both GRP and NMB (p = 0.048). HBE cultures from subjects with a greater than 25 PY smoking history were also more likely to respond to BLPs in the proliferation assays than cells from subjects with less than a 25 PY history (10 of 16 versus 1 of 7, p = 0.06). Cultures of HBE cells from four of the five subjects with severe obstructive lung disease gave a positive response to GRP and NMB in proliferation assays, compared to five of fifteen without severe obstructive lung disease, but this difference was not significant (p = 0.13). These results suggest there is an increased likelihood of expression of the GRP receptor mRNA in the respiratory epithelium of some individuals with a history of prolonged tobacco exposure, and that expression of the GRP receptor mRNA is accompanied by responsiveness to the mitogenic effects of BLPs. These effects appear to persist after smoking cessation.
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PMID:Expression of mRNA for gastrin-releasing peptide receptor by human bronchial epithelial cells. Association with prolonged tobacco exposure and responsiveness to bombesin-like peptides. 927 10

KL-6 in serum and bronchoalveolar lavage fluid has been reported to be a sensitive marker indicating the activity of fibrosing lung diseases. The molecule is clustered in MUC1 mucin according to the findings of immunohistochemical and cytometric studies. To elucidate the pathogenic role of KL-6 in fibrosing lung disease, we characterized its biochemical properties and examined whether purified KL-6 is chemotactic for human fibroblasts in vitro using modified Boyden chambers. Biochemical properties of purified KL-6 were similar to those of other MUC1 mucins previously reported. KL-6 promoted the migration of 5 of 5 human lung fibroblasts and 3 of 4 human skin fibroblasts. Checkerboard analysis revealed that KL-6 was chemotactic as well as chemokinetic. Though platelet-derived growth factor, fibroblast growth factor, or fibronectin were also chemotactic for fibroblasts in the experimental system, only fibronectin augmented KL-6-induced chemotaxis. These observations indicate that KL-6 is one of the chemotactic factors for most fibroblasts and that the increased KL-6 in the epithelial lining fluid in small airways may cause the intra-alveolar fibrosis in fibrosing lung diseases.
Am J Respir Cell Mol Biol 1997 Oct
PMID:KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. 937 25

Human interleukin 13 (IL-13) is a cytokine that has a profound effect on primary immune cells by inducing immunoglobulin production, proliferation of B cells, and the differentiation of cells of the monocytic lineage. IL-13 can inhibit the production of inflammatory cytokines by both macrophages and monocytes. Previously, IL-13 expression has been reported only in cells of the T-cell lineage and the mast cell line HMC-1. We now report the presence of IL-13 mRNA and protein in human alveolar macrophages (AMs) analyzed by the reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunoabsorbent assay (ELISA), respectively, and IL-13 protein in bronchoalveolar lavage fluid (BALF) of subjects with pulmonary fibrosis. We have investigated 13 patients from 49 to 75 yr of age with forms of pulmonary fibrosis, and eight healthy volunteers from 24 to 61 yr of age. Their AMs were obtained by bronchoalveolar lavage (BAL) and purified by adherence. The proportion of BAL purified AMs expressing IL-13 mRNA was increased in those subjects with fibrotic lung disease, in comparison with those from control subjects (11 of 13 versus 2 of 8, P < 0.01). IL-13 protein was detectable in the BALF of 8 of 13 patients with pulmonary fibrosis, but in none of the control subjects. AMs of four subjects with systemic sclerosis were cultured and IL-13 protein was increased in the culture supernatants when compared to the control subjects, although this did not reach significance. These findings show that IL-13 mRNA is not only a product of T cells, but is also expressed in both normal AMs and those from subjects with pulmonary fibrosis, and that at least some of the IL-13 mRNA is translated into protein and secreted in subjects with pulmonary fibrosis. We hypothesize that IL-13 may be expressed by normal human AMs as part of the homeostatic control process but its production may be increased in the presence of inflammatory lung disease.
Am J Respir Cell Mol Biol 1998 Jan
PMID:Production of interleukin 13 by alveolar macrophages from normal and fibrotic lung. 944 46

Annexin I is a 36 kilodalton (kD) calcium-dependent phospholipid-binding protein which may have anti-inflammatory properties. Previous investigations which sampled lower respiratory tract epithelial lining fluid (ELF) via bronchoalveolar lavage (BAL) have demonstrated that annexin I can be degraded in inflammatory lung disease. We analyzed BAL fluid from patients with cystic fibrosis (CF) to determine the effects of lung inflammation on the structure and activity of annexin I. Intact annexin I was absent in 17 out of 20 BAL fluid samples from patients with CF, due largely to degradation to a 33 kD protein. The three CF BAL fluids in which annexin I was detectable had very little or no unopposed neutrophil elastase activity in contrast to the 17 in which no annexin I was detectable. Annexin I was present in all BAL fluid samples from 10 normal volunteer (NV) subjects and 12 patients with interstitial lung disease (ILD). The 33 kD annexin I breakdown product was not detectable in samples from NV, but was detectable only in ILD patients with relatively high percentages of neutrophils on BAL differential cell counts. Annexin I appeared to be cleaved by neutrophil elastase at the N-terminal portion between Val-36 and Ser-37 to yield the 33 kD protein. Cleavage of the N-terminal portion of annexin I was accompanied by a marked change in the annexin I isoelectric point (pI) value (from 6.0 to 8.5-9.0) and greatly diminished annexin I functional activity. Our findings demonstrate that annexin I degradation in epithelial lining fluid is closely related to lung inflammation.
Am J Respir Cell Mol Biol 1998 Jan
PMID:Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis. 944 53

Pulmonary complications are a major clinical problem following allogeneic bone marrow transplantation (BMT), contributing to more than 30% of transplant-related mortalities. Idiopathic pneumonia syndrome is responsible for significant mortality among BMT patients. However, the etiology of injury to the lung parenchyma by this disease syndrome is unknown and it has been difficult to evaluate the cellular and molecular mechanisms underlying IPS in the absence of a suitable animal model. To study post-BMT lung disease during graft-versus-host disease (GVHD), we have developed a murine model that utilizes a semi-allogeneic parental --> F1 transplant strategy to induce a mild form of GVHD. Progressive inflammatory lung disease developed in animals with mild GVHD, as indicated by changes in immune cell distribution and cytokine expression in the lungs of transplanted animals. Histologic analysis of lung tissue from GVHD mice at 3 wk post-BMT showed minor immunopathologic changes compared with control mice. In contrast, lungs of GVHD mice at 12 wk displayed histopathologic hallmarks of interstitial pneumonitis, such as prominent perilumenal mononuclear cell infiltration and areas of alveolar congestion. Flow cytometric analysis of lung interstitial cells of GVHD mice revealed an increase in CD8+ T-cells at week 3, which decreased to normal levels by week 12 post-BMT. Simultaneously, the percentage of CD4+ T-cells increased progressively above normal levels and peaked at week 7 post-BMT. Analysis of cytokine mRNA expression in lung tissue indicated that steady state levels of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, interferon-gamma, and IL-12 were significantly elevated in lungs of GVHD mice at 3 wk post-BMT compared with untreated controls. Mice that were transplanted with allogeneic bone marrow alone (BMT controls) also displayed elevated expression of these cytokines, although only IL-6 was significantly higher than in untreated controls. In contrast, at 12 wk after transplantation only TNF-alpha and IL-12 levels remained elevated in GVHD mice, suggesting prolonged macrophage activation. On the basis of these findings, we conclude that allogeneic bone marrow transplantation in this mouse model causes a progressive interstitial pneumonitis, which is characterized by an acute influx of CD8+ T-cells, followed in the chronic phase by a prominent accumulation of CD4+ T-cells, and is associated with persistent production of cytokines known to activate macrophages.
Am J Respir Cell Mol Biol 1998 Feb
PMID:Idiopathic pneumonia syndrome in mice after allogeneic bone marrow transplantation. 947 11

It is now recognized that respiratory muscle fatigue contributes to the development of respiratory failure in some patients with lung disease. This observation has prompted an examination into the mechanisms of development of muscle fatigue, with the understanding that an elucidation of these processes may lead to new therapeutic approaches to the treatment of these patients. A series of recent studies examining this issue have, moreover, discovered that oxygen-derived free radicals generated during strenuous contraction may modulate respiratory muscle contractile function and contribute to the development of muscle fatigue. The data supporting this concept include: (a) direct (e.g. EPR, ESR studies) and indirect (evidence of lipid peroxidation, protein carbonyl formation, glutathione oxidation) evidence that there is heightened free radical production in contracting muscle, (b) evidence that pharmacologic depletion of muscle antioxidant stores increases degree of muscle fatigue present after a period of exercise, and (c) evidence that administration of agents that act as free radical scavengers retard the development muscle fatigue. Free radicals may produce these changes in muscle force generating capacity by interacting with and altering the function of a number of intracellular-biophysical processes (i.e. sarcolemmal action potential propagation, sarcoplasmic reticulum calcium handling, mitochondrial function, contractile protein interactions).
Mol Cell Biochem 1998 Feb
PMID:Free radical induced respiratory muscle dysfunction. 954 53

Cystic fibrosis (CF) has emerged as a paradigm disorder for assessing the utility of gene therapy in the treatment of genetic diseases. It is hypothesized that submucosal glands may play an important role in the pathophysiology of CF lung disease. However, this region poses several significant obstacles for gene therapy due to its inaccessibility from the lumen of adult proximal airways. In utero gene therapy to correct submucosal gland dysfunction in CF provides an attractive alternative strategy to target gland progenitor cells prior to gland formation and morphogenesis. Such approaches will require the use of integrating vectors capable of transducing expanding stem-cell/progenitor-cell populations in the lung. We described a newborn-ferret model of the proximal airway which was used to evaluate the phenotypic characteristics of submucosal gland progenitors and to test gene therapy strategies for targeting these cell types. To this end, we have isolated the ferret cDNA to the lymphoid enhancing factor 1 (Lef1) and have demonstrated that its mRNA expression specifically defines a subset of surface airway epithelial progenitor cells involved in the formation of primordial submucosal gland buds and subsequent gland morphogenesis. Such findings suggest that the transcriptional switch regulating activation of Lef1 expression defines the phenotype of early submucosal gland progenitor cells. In an effort to prove the principle of gene targeting to this progenitor-cell population, we evaluated the efficiency of recombinant retroviral vectors to target submucosal glands in a xenograft model system. Findings from these studies demonstrated successful gene targeting to progenitor cells of submucosal gland buds which was stable throughout subsequent gland development. In summary, these studies have provided evidence for the existence of phenotypically distinct submucosal gland progenitor cells which represent appropriate targets for gene therapy of submucosal glands in CF.
Am J Respir Cell Mol Biol 1998 Jun
PMID:Lef1 transcription factor expression defines airway progenitor cell targets for in utero gene therapy of submucosal gland in cystic fibrosis. 961 79

Mast cells are traditionally known for mediating allergic reactions. In addition, these cells have been implicated in the pathogenesis of a variety of clinical conditions such as atopic and contact dermatitis, bullous pemphigoid, fibrotic lung disease, neurofibromatosis, psoriasis, scleroderma, rheumatoid arthritis, interstitial cystitis, ulcerative colitis, and Crohn's disease, but their role in host defense was an enigma until recently. Owing to the strategic location of mast cells at the host environment interface, their role in bacterial infections has been studied by a number of investigators. Latest reports show that mast cells have an ability to modulate the host's innate immune response to infectious agents. This review discusses the clinical implications of mast cell-bacteria interactions.
J Mol Med (Berl) 1998 Aug
PMID:Clinical implications of mast cell-bacteria interaction. 972 64


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