An Immunohistochemical Study of Architectural Remodeling and Connective Tissue Synthesis in Pulmonary Fibrosis

Kuhn, Charles; Boldt, J.; King, Talmadge E.; Crouch, Edmond C.; Vartio, T; McDonald, John A.

doi:10.1164/ajrccm/140.6.1693

Cited by 424 publications

(243 citation statements)

References 14 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: 96%

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: 96%

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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“…The increase of collagen and other components of extracellular matrix occur as a tissue response to injury and can lead to fibrosis of the organ. Previous studies have demonstrated that collagen synthesis is increased in pulmonary fibrosis (7), in glomerulosclerosis (8) and in other pathologies.…”

Section: Introductionmentioning

confidence: 97%

Stereological study of collagen and elastic system in the detrusor muscle of bladders from controls and patients with infravesical obstruction

2007

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Objective: Compare detrusor muscle of normal and patients with infravesical obstruction, quantifying the collagen and elastic system fibers. Materials and Methods:We studied samples taken from bladders of 10 patients whose ages ranged from 45 to 75 years (mean = 60 years), who underwent transvesical prostatectomy for treatment of BPH. Control material was composed of 10 vesical specimens, removed during autopsies performed in cadavers of accident victims, with ages between 18 and 35 years (mean = 26 years). Results:The results of collagen and elastic fibers quantification (volumetric density) demonstrated the following results in percentage (mean +/-standard deviation): collagen in BPH patients = 4.89 +/-2.64 and 2.32 +/-1.25 in controls (p < 0.0001), elastin in BPH patients = 10.63% +/-2.00 and 8.94% +/-1.19 in controls (p < 0.0001). Conclusion:We found that the components of connective tissue, collagen and elastic system fibers are increased in the detrusor muscle of patients with infravesical obstruction, when compared to controls.

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“…The ECM is a highly dynamic complex that varies in composition according to its tissue localization and physiologic circumstances. Collagens are the predominant ECM proteins identified in fibrotic lesions and are the hallmark of fibroproliferative diseases, but fibronectins (FNs) are also present in abnormally large quantities and localize to areas of active fibrogenesis (3,4).…”

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confidence: 99%

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

Muro¹,

Moretti²,

Moore³

et al. 2008

Am J Respir Crit Care Med

265

254

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Rationale: Tissue fibrosis is considered a dysregulated wound-healing response. Fibronectin containing extra type III domain A (EDA) is implicated in the regulation of wound healing. EDA-containing fibronectin is deposited during wound repair, and its presence precedes that of collagen. Objectives: To investigate the role of EDA-containing fibronectin in lung fibrogenesis. Methods: Primary lung fibroblasts from patients with idiopathic pulmonary fibrosis or from patients undergoing resection for lung cancer were assessed for EDA-containing fibronectin and a-smooth muscle actin (a-SMA) expression. Mice lacking the EDA domain of fibronectin and their wild-type littermates were challenged with the bleomycin model of lung fibrosis. Primary lung fibroblasts from these mice were assayed in vitro to determine the contribution of EDA-containing fibronectin to fibroblast phenotypes. Measurements and Main Results: Idiopathic pulmonary fibrosis lung fibroblasts produced markedly more EDA-containing fibronectin and a-SMA than control fibroblasts. EDA-null mice failed to develop significant fibrosis 21 days after bleomycin challenge, whereas wildtype controls developed the expected increase in total lung collagen. Histologic analysis of EDA-null lungs after bleomycin showed less collagen and fewer a-SMA-expressing myofibroblasts compared with that observed in wild-type mice. Failure to develop lung fibrosis in EDA-null mice correlated with diminished activation of latent transforming growth factor (TGF)-b and decreased lung fibroblast responsiveness to active TGF-b in vitro. Conclusions: The data show that EDA-containing fibronectin is essential for the fibrotic resolution of lung injury through TGF-b activation and responsiveness, and suggest that EDA-containing fibronectin plays a critical role in tissue fibrogenesis.Keywords: fibrosis; fibronectin; TGF-b; myofibroblast Fibroproliferative disorders, characterized by the increased production and deposition of extracellular matrix (ECM) proteins in tissues, are not well understood despite major efforts to elucidate pathogenic mechanisms. Recent attention has focused on ECM components and mesenchymal cell phenotypes as being critical to the development of fibrosis (1, 2). The ECM is a highly dynamic complex that varies in composition according to its tissue localization and physiologic circumstances. Collagens are the predominant ECM proteins identified in fibrotic lesions and are the hallmark of fibroproliferative diseases, but fibronectins (FNs) are also present in abnormally large quantities and localize to areas of active fibrogenesis (3, 4).FNs are multifunctional glycoproteins found in the ECM of tissues and plasma. Two main forms of FN exist: plasma FN, a dimeric and soluble form produced by hepatocytes that lacks the EDA and EDB sequences, and cellular FN (cFN), a multimeric form synthesized by mesenchymal, epithelial, and inflammatory cells, which is deposited in ECM fibrils and that contains variable proportions of the extra type III domains A and B (EDA and EDB) (5...

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An Immunohistochemical Study of Architectural Remodeling and Connective Tissue Synthesis in Pulmonary Fibrosis

Cited by 424 publications

References 14 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

Stereological study of collagen and elastic system in the detrusor muscle of bladders from controls and patients with infravesical obstruction

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

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