Cytokine Networks in the Regulation of Inflammation and Fibrosis in the Lung

Elias, Jack A.; Freundlich, Bruce; Kern, Jeffrey A.; Rosenbloom, Joel

doi:10.1378/chest.97.6.1439

Cited by 247 publications

(130 citation statements)

References 22 publications

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“…This observation is also of considerable interest considering that increased procollagen type III occurs early in pulmonary fibrosis and is thought to be predictive of fibrotic diseases in the lung. 49,70 Although constitutive levels of TGF-␤ did not differ between the two types of fibroblasts, levels of this cytokine were approximately sevenfold higher in cultures of IL-4-stimulated fibroblasts from L-NAME-treated mice compared with their D-NAMEtreated counterparts. Furthermore, in vitro IFN-␥ treatment of fibroblasts from L-NAME-treated mice did not abolish TGF-␤ synthesis.…”

Section: Discussionmentioning

confidence: 92%

“…The onset of fibrosis during clinical or experimental lung disease appears to follow increases in IL-4, tumor necrosis factor-␣ and TGF-␤ levels. 49 Experimental pulmonary granuloma formation is also dependent on the initial cytokine profile elicited. 1,38 The PPD-bead granulomatous response is initially dominated by IFN-␥ with little IL-4 synthesis, and this lesion typically resolves without evidence of extracellular matrix deposition around the bead.…”

Section: Discussionmentioning

confidence: 99%

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Collagen Deposition in a Non-Fibrotic Lung Granuloma Model after Nitric Oxide Inhibition

Hogaboam

Gallinat

Bone-Larson

et al. 1998

The American Journal of Pathology

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Recent studies support the concept that pulmonary granulomatous inflammation directed by interferon (IFN)-␥, interleukin (IL)-12, and nitric oxide usually resolves in the absence of fibrosis. To determine whether nitric oxide participates in modulating the fibrotic response during the development of pulmonary granulomas in response to purified protein derivative (PPD) , mice presensitized to PPD received daily intraperitoneal injections of N G -nitro-D-arginine-methyl ester (D-NAME) , N G -nitro-L-argininemethyl ester (L-NAME) , or aminoguanidine after delivery of PPD-coated beads to the lungs. Eight days later , morphometric analysis of lung granulomas revealed that L-NAME-treated mice when challenged with PPD in vitro for 36 hours had the largest pulmonary granulomas and the greatest collagen deposition among the treated groups. In addition , equivalent numbers of dispersed lung cells from L-NAME-and aminoguanidine-treated mice produced significantly higher levels of IL-4 , monocyte chemoattractant protein (MCP)-1 , and macrophage inflammatory protein (MIP)-1␣ and significantly lower levels of eotaxin compared with D-NAME-treated mice. Cultures of dispersed lung cells from L-NAME-treated mice also produced significantly more IL-10 and less IL-12 compared with similar numbers of dispersed lung cells from D-NAME-treated mice. Cultures of isolated lung fibroblasts from L-NAME-treated mice expressed higher levels of C-C chemokine receptor 2 (CCR2) and CCR3 mRNA and contained less MCP-1 and eotaxin protein than a similar number of fibroblasts from D-NAME-treated mice. Thus , nitric oxide appears to regulate the deposition of extracellular matrix in lung granulomas through the modulation of the cytokine and chemokine profile of these lesions. Alterations in the cytokine , chemokine , and procollagen profile of this lesion may be a direct effect of nitric oxide on the pulmonary fibroblast and provide an important signal for regulating fibroblast activity during the evolu- It is not uncommon for chronic pulmonary granulomatous inflammation to result in irreversible tissue injury and end-stage fibrosis. 1 For reasons that are presently unclear, the reparative process associated with interstitial pulmonary inflammation can progress uncontrollably, as evidenced by increased lung fibroblast proliferation and the deposition of collagenous material. 2 Clinical and laboratory evidence suggest that the progressive and unregulated reparative process in the lung is potentially related to the persistence of a variety of inflammatory signals. 3 Unfortunately, clinical strategies directed at preventing deleterious fibrotic responses through the nonselective inhibition of the inflammatory process with corticosteroid, cyclophosphamide, and azathioprine treatments have been both largely unsuccessful and often associated with severe side effects. 4 Previous studies of experimental, antigen-driven granulomatous pulmonary inflammatory responses has demonstrated that inflammatory cytokine profiles have a major role in the degree of extra...

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Collagen Deposition in a Non-Fibrotic Lung Granuloma Model after Nitric Oxide Inhibition

Hogaboam

Gallinat

Bone-Larson

et al. 1998

The American Journal of Pathology

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“…Several proinflammatory cytokines including IL-1␤ and TNF-␣ are involved in pulmonary inflammation and the subsequent development of pulmonary fibrosis in a mouse model of BLM-induced pulmonary fibrosis (3,11,18). A previous study showed that continuous infusion of an IL-1 receptor antagonist prevented BLM-induced pulmonary fibrosis (19).…”

Section: Discussionmentioning

confidence: 99%

C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice

Murakami¹,

Nagaya²,

Itoh³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Murakami, Shinsuke, Noritoshi Nagaya, Takefumi Itoh, Takafumi Fujii, Takashi Iwase, Kaoru Hamada, Hiroshi Kimura, and Kenji Kangawa. C-type natriuretic peptide attenuates bleomycininduced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 287: L1172-L1177, 2004. First published July 30, 2004 doi:10.1152/ajplung.00087.2004.-C-type natriuretic peptide (CNP) has been shown to play an important role in the regulation of vascular tone and remodeling. However, the physiological role of CNP in the lung remains unknown. Accordingly, we investigated whether CNP infusion attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. After intratracheal injection of BLM or saline, mice were randomized to receive continuous infusion of CNP or vehicle for 14 days. CNP infusion significantly reduced the total number of cells and the numbers of macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid. Interestingly, CNP markedly reduced bronchoalveolar lavage fluid IL-1␤ levels. Immunohistochemical analysis demonstrated that CNP significantly inhibited infiltration of macrophages into the alveolar and interstitial regions. CNP infusion significantly attenuated BLM-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. CNP markedly decreased the number of Ki-67-positive cells in fibrotic lesions of the lung, suggesting antiproliferative effects of CNP on pulmonary fibrosis. Kaplan-Meier survival curves demonstrated that BLM mice treated with CNP had a significantly higher survival rate than those given vehicle. These results suggest that continuous infusion of CNP attenuates BLM-induced pulmonary fibrosis and improves survival in BLM mice, at least in part by inhibition of pulmonary inflammation and cell proliferation.

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“…Our data show that activation of upstream pathways such as IKK or MAPKs and TFs (NF-κB, AP-1) is associated with simultaneous increases in gene transcription of cytokines IL-1, IL-6, and TNF-α, which are not only important pro-inflammatory cytokines but also known to stimulate fibroblast proliferation and extracellular matrix production (Elias et al, 1990;Postlethwaite and Seyer, 1990;Chen et al, 1998), and along with up-regulation of TGF-β1 reported earlier (Khan et al, 2003b), could be important in the initiation of a fibrogenic response in the spleen following exposure to aniline.…”

Section: Discussionmentioning

confidence: 78%

Activation of oxidative stress-responsive signaling pathways in early splenotoxic response of aniline

Wang

Ansari

et al. 2008

Toxicology and Applied Pharmacology

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Aniline exposure causes toxicity to the spleen, which leads to a variety of sarcomas, and fibrosis appears to be an important preneoplastic lesion. However, early molecular mechanisms in anilineinduced toxicity to the spleen are not known. Previously, we have shown that aniline exposure results in iron overload and induction of oxidative stress in the spleen, which can cause transcriptional upregulation of fibrogenic/inflammatory cytokines via activation of oxidative stress (OS)-responsive signaling pathways. To test this mechanism, male SD rats were treated with aniline (1 mmol/kg/day via gavage) for 7 days, an experimental condition that precedes the appearance of fibrosis. Significant increases in both NF-κB and AP-1 binding activity was observed in the nuclear extracts of splenocytes from aniline-treated rats as determined by ELISAs, and supported by Western blot data showing increases in p-IκBα, p-p65 and p-c-Jun. To understand the upstream signaling events which could account for the activation of NF-κB and AP-1, phosphorylation patterns of IκB kinases (IKKα and IKKβ) and mitogen-activated protein kinases (MAPKs) were pursued. Our data showed remarkable increases in both p-IKKα and p-IKKβ in the splenocytes from aniline-treated rats, suggesting their role in the phosphorylation of both IκBα and p65 subunits. Furthermore, aniline exposure led to activation of all three classes of MAPKs, as evident from increased phosphorylation of extracellularsignal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK1/2) and p38 MAPKs, which could potentially contribute to the observed activation of both AP-1 and NF-κB. Activation of upstream signaling molecules was also associated with simultaneous increases in gene transcription of cytokines IL-1, IL-6 and TNF-α. The observed sequence of events following aniline exposure could initiate a fibrogenic and/or tumorigenic response in the spleen.

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Cytokine Networks in the Regulation of Inflammation and Fibrosis in the Lung

Cited by 247 publications

References 22 publications

Collagen Deposition in a Non-Fibrotic Lung Granuloma Model after Nitric Oxide Inhibition

Collagen Deposition in a Non-Fibrotic Lung Granuloma Model after Nitric Oxide Inhibition

C-type natriuretic peptide attenuates bleomycin-induced pulmonary fibrosis in mice

Activation of oxidative stress-responsive signaling pathways in early splenotoxic response of aniline

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