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Mechanisms Involved in Granuloma and Fibrosis Resolution: Spontaneous or Mediated

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 10626

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Dr. Anagha Malur

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Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, The Brody School of Medicine, East Carolina University, Greenville, NC, USA
Interests: sarcoid; asthma and pulmonary; hypertension; sarcoidosis; granuloma
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Dear Colleagues,

The recent literature on granuloma formation and fibrosis has evolved and indicated they can be mediated by environmental factors and triggers. The long-term analysis of mediators involving their resolution of granuloma and fibrosis represents a poorly addressed area. Multiple immune cells are shown to be involved in regulating the development of granuloma formation and fibrosis, such as macrophages, lymphocytes, neutrophils, and some subtypes of these cells. The actual role of these cells in granulomas are not clear. In addition, a large number of cytokines and chemokines play an important role in the progression from recurrent inflammation to fibrosis. However, the network of those immune cells and cytokines is remains underinvestigated.

For this Special Issue, we welcome submissions on mechanisms that could possibly be involved in resolution, including the molecular basis of the interaction of the innate and adaptive immune responses. Animal studies, in vitro studies, and clinical studies addressing this resolution will help in delineating pathways which could lead to potential studies toward clinical trials.

Dr. Anagha Malur
Guest Editor

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Keywords

granuloma
fibrosis
inflammation
immune regulation

Published Papers (4 papers)

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Research

21 pages, 1507 KiB

Open AccessArticle

Water from Nitrodi’s Spring Induces Dermal Fibroblast and Keratinocyte Activation, Thus Promoting Wound Repair in the Skin: An In Vitro Study

by Filomena Napolitano, Loredana Postiglione, Ilaria Mormile, Valentina Barrella, Amato de Paulis, Nunzia Montuori and Francesca Wanda Rossi

Int. J. Mol. Sci. 2023, 24(6), 5357; https://doi.org/10.3390/ijms24065357 - 10 Mar 2023

Cited by 3 | Viewed by 1646

Abstract

The Romans knew of Nitrodi’s spring on the island of Ischia more than 2000 years ago. Although the health benefits attributed to Nitrodi’s water are numerous, the underlying mechanisms are still not understood. In this study, we aim to analyze the physicochemical properties and biological effects of Nitrodi’s water on human dermal fibroblasts to determine whether the water exerts in vitro effects that could be relevant to skin wound healing. The results obtained from the study indicate that Nitrodi’s water exerts strong promotional effects on dermal fibroblast viability and a significant stimulatory activity on cell migration. Nitrodi’s water induces alpha-SMA expression in dermal fibroblasts, thus promoting their transition to myofibroblast-protein ECM deposition. Furthermore, Nitrodi’s water reduces intracellular reactive oxygen species (ROS), which play an important role in human skin aging and dermal damage. Unsurprisingly, Nitrodi’s water has significant stimulatory effects on the cell proliferation of epidermal keratinocytes and inhibits the basal ROS production but enhances their response to the oxidative stress caused by external stimuli. Our results will contribute to the development of human clinical trials and further in vitro studies to identify inorganic and/or organic compounds responsible for pharmacological effects. Full article

(This article belongs to the Special Issue Mechanisms Involved in Granuloma and Fibrosis Resolution: Spontaneous or Mediated)

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18 pages, 29461 KiB

Open AccessArticle

Myeloid ABCG1 Deficiency Enhances Apoptosis and Initiates Efferocytosis in Bronchoalveolar Lavage Cells of Murine Multi-Walled Carbon Nanotube-Induced Granuloma Model

by Eman Soliman, Sophia Bhalla, Ahmed E. M. Elhassanny, Anagha Malur, David Ogburn, Nancy Leffler, Achut G. Malur and Mary Jane Thomassen

Int. J. Mol. Sci. 2022, 23(1), 47; https://doi.org/10.3390/ijms23010047 - 21 Dec 2021

Cited by 7 | Viewed by 3079

Abstract

The use of carbon nanotubes has increased in the past few decades. Carbon nanotubes are implicated in the pathogenesis of pulmonary sarcoidosis, a chronic granulomatous inflammatory condition. We developed a murine model of chronic granulomatous inflammation using multiwall carbon nanotubes (MWCNT) to investigate mechanisms of granuloma formation. Using this model, we demonstrated that myeloid deficiency of ATP-binding cassette (ABC) cholesterol transporter (ABCG1) promotes granuloma formation and fibrosis with MWCNT instillation; however, the mechanism remains unclear. Our previous studies showed that MWCNT induced apoptosis in bronchoalveolar lavage (BAL) cells of wild-type (C57BL/6) mice. Given that continual apoptosis causes persistent severe lung inflammation, we hypothesized that ABCG1 deficiency would increase MWCNT-induced apoptosis thereby promoting granulomatous inflammation and fibrosis. To test our hypothesis, we utilized myeloid-specific ABCG1 knockout (ABCG1 KO) mice. Our results demonstrate that MWCNT instillation enhances pulmonary fibrosis in ABCG1 KO mice compared to wild-type controls. Enhanced fibrosis is indicated by increased trichrome staining and transforming growth factor-beta (TGF-β) expression in lungs, together with an increased expression of TGF-β related signaling molecules, interleukin-13 (IL-13) and Smad-3. MWCNT induced more apoptosis in BAL cells of ABCG1 KO mice. Initiation of apoptosis is most likely mediated by the extrinsic pathway since caspase 8 activity and Fas expression are significantly higher in MWCNT instilled ABCG1 KO mice compared to the wild type. In addition, TUNEL staining shows that ABCG1 KO mice instilled with MWCNT have a higher percentage of TUNEL positive BAL cells and more efferocytosis than the WT control. Furthermore, BAL cells of ABCG1 KO mice instilled with MWCNT exhibit an increase in efferocytosis markers, milk fat globule-EGF factor 8 (MFG-E8) and integrin β3. Therefore, our observations suggest that ABCG1 deficiency promotes pulmonary fibrosis by MWCNT, and this effect may be due to an increase in apoptosis and efferocytosis in BAL cells. Full article

(This article belongs to the Special Issue Mechanisms Involved in Granuloma and Fibrosis Resolution: Spontaneous or Mediated)

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16 pages, 5611 KiB

Open AccessArticle

The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in Mmp12 Knock-Out Mice Instilled with Multiwall Carbon Nanotubes

by David Ogburn, Sophia Bhalla, Nan Leffler, Arjun Mohan, Anagha Malur, Achut G. Malur, Matthew McPeek, Barbara P. Barna and Mary Jane Thomassen

Int. J. Mol. Sci. 2021, 22(20), 11019; https://doi.org/10.3390/ijms222011019 - 13 Oct 2021

Cited by 2 | Viewed by 2170

Abstract

Sarcoidosis is a chronic disease with unknown etiology and pathophysiology, characterized by granuloma formation. Matrix Metalloproteinase-12 (MMP12) is an elastase implicated in active granulomatous sarcoidosis. Previously, we reported that oropharyngeal instillation of multiwall carbon nanotubes (MWCNT) into C57Bl/6 mice induced sarcoid-like granulomas and upregulation of MMP12. When Mmp12 knock-out (KO) mice were instilled with MWCNT, granuloma formation occurred 10 days post-instillation but subsequently resolved at 60 days. Thus, we concluded that MMP12 was essential to granuloma persistence. The aim of the current study was to identify potential mechanisms of granuloma resolution in Mmp12KO mice. Strikingly, an M2 macrophage phenotype was present in Mmp12KO but not in C57Bl/6 mice. Between 10 and 60 days, macrophage populations in MWCNT-instilled Mmp12KO mice demonstrated an M2c to M2a phenotypic shift, with elevations in levels of IL-13, an M2 subtype-regulating factor. Furthermore, the M2 inducer, Apolipoprotein E (ApoE), and Matrix Metalloproteinase-14 (MMP14), a promoter of collagen degradation, were upregulated in 60-day MWCNT-instilled Mmp12KO mice. In conclusion, alveolar macrophages express two M2 phenotypes in Mmp12KO mice: M2c at 10 days when granulomas form, and M2a at 60 days when granulomas are resolving. Findings suggest that granuloma resolution in 60-day Mmp12KO mice requires an M2a macrophage phenotype. Full article

(This article belongs to the Special Issue Mechanisms Involved in Granuloma and Fibrosis Resolution: Spontaneous or Mediated)

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15 pages, 4333 KiB

Open AccessArticle

Tauroursodeoxycholic Acid Decreases Keloid Formation by Reducing Endoplasmic Reticulum Stress as Implicated in the Pathogenesis of Keloid

by Sunje Kim, Seong Eun Lee, Shinae Yi, Sangmi Jun, Yoon-Sun Yi, Harsha Nagar, Cuk-Seong Kim, Chungmin Shin, Min-Kyung Yeo, Yea Eun Kang and Sang-Ha Oh

Int. J. Mol. Sci. 2021, 22(19), 10765; https://doi.org/10.3390/ijms221910765 - 5 Oct 2021

Cited by 10 | Viewed by 2935

Abstract

Keloids are a common form of pathologic wound healing and are characterized by an excessive production of extracellular matrix. This study examined the major contributing mechanism of human keloid pathogenesis using transcriptomic analysis. We identified the upregulation of mitochondrial oxidative stress response, protein processing in the endoplasmic reticulum, and TGF-β signaling in human keloid tissue samples compared to controls, based on ingenuity pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Electron microscopic examinations revealed an increased number of dysmorphic mitochondria and expanded endoplasmic reticulum (ER) in human keloid tissue samples than that in controls. Western blot analysis performed using human tissues suggested noticeably higher ER stress signaling in keloids than in normal tissues. Treatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, significantly decreased scar formation in rabbit models, compared to normal saline and steroid injections. In summary, our findings demonstrate the contributions of mitochondrial dysfunction and dysregulated ER stress signaling in human keloid formation and the potential of TUDCA in the treatment of keloids. Full article

(This article belongs to the Special Issue Mechanisms Involved in Granuloma and Fibrosis Resolution: Spontaneous or Mediated)

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