Dysregulated inflammatory response in pulmonary hypertension is still enigmatic: what about psoriasin?

PVRI Member Authors: Djuro Kosanovic, Michael Seimetz, Oleg Pak, Himal Luitel, Akylbek Sydykov, Norbert Weissmann, Ralph T. Schermuly

Prelude

Altered regulation of the immune system and enhanced inflammation were recognized as important characteristics of the pulmonary hypertension (PH) pathology.1-5 However, many underlying molecular mechanisms responsible for such uncontrolled inflammatory response in this incurable pulmonary vascular disease remained unclear and need to be further enlighten. Psoriasin (S100A7), a molecular mediator discovered over two decades ago in the pathology of psoriasis, plays a significant role in innate immunity and antimicrobial battle, skin inflammation and tumor development and progression.6-10 Due to its potent pro-inflammatory power one can expect that psoriasin may represent a novel culprit involved in the PH pathogenesis. However, up to date nothing is known regarding its potential role in the context of pulmonary vascular disease. Therefore, we would like to mobilize the scientists interested in this topic to share their valuable views and knowledge in order to unravel whether psoriasin can represent a promising target for the future investigation.

Main Article

 Despite its beneficial role as a part of the immune system defense against microorganisms, overexpression of psoriasin was found to be responsible for increased tumor growth and metastasis via orchestration of various inflammatory and pro-proliferative pathways/ mediators and events, such as increased CCL2 (chemokine (C-C motif) ligand 2)/MCP-1 (monocyte chemotactic protein-1), MMP- 9 (matrix metalloproteinase-9) and VEGF (vascular endothelial growth factor), and promoted chemotaxis of macrophages9 . In the context of PH, it is worth to mention that CCL2/ MCP-1, MMP-9 and abnormal accumulation of macrophages are already described, suggesting the hypothetical link between psoriasin and pulmonary vascular disease (Figure 1).2, 11-13 Furthermore, it was demonstrated that psoriasin stimulated neutrophil-associated production of different cytokines and chemokines, particularly IL-6 (interleukin-6) and TNF-α (tumor necrosis factor-α).14 IL-6 and TNF-α are important culprits for the PH development, indicating another theoretical possibility how psoriasin could contribute to the pathology of the pulmonary circulation (Figure 1).15, 16 Shifting from the cancer field to the lungs and respiratory disorders, psoriasin was found to be expressed in the lung epithelial cells and macrophages.17 Interestingly, psoriasin profile did not change in the patients with chronic obstructive pulmonary disease, compared to the healthy controls.17 Surprisingly, one has also to keep in mind the existence of potentially antifibrotic effects of psoriasin.10 Finally, the literature suggested that reactive oxygen species (ROS), an important feature of the PH pathobiology, are also described as inducers of psoriasin.18-20 Even more, psoriasin itself was shown to induce ROS production in epithelial and endothelial cells, indicating the probable existence of the positive loop between ROS and psoriasin.18 In addition, it was found that psoriasin acting via receptor for advanced glycation end products (RAGE) leads to augmented proliferation of endothelial cells and further increase of ROS.18 Following this line of thinking, it is worth to mention that dysregulated endothelial cells and injured endothelium are indeed involved in the complex PH pathology, so one can hypothesize that similar effects of psoriasin may be possible in the context of the pulmonary vascular endothelium (Figure 1).18, 21

 

Capture1.JPG

Figure 1. Hypothetical involvement of psoriasin in the pathobiology of pulmonary hypertension. ROS: reactive oxygen species; M: macrophages; N: neutrophils; RAGE: receptor for advanced glycation end products; PH: pulmonary hypertension; MMP-9: matrix metalloproteinase-9; VEGF: vascular endothelial growth factor; CCL2: chemokine (C-C motif) ligand 2; MCP-1: monocyte chemotactic protein-1.

In conclusion, we propose that psoriasin, due to its potent pro-inflammatory and pro-proliferative properties acts as a molecular conductor in orchestration of different signals and events, such as ROS, inflammatory cells accumulation, cytokines, chemokines etc. in the pathological opera of the pulmonary vascular remodeling (Figure 1).

The Question for interactive discussion:

 We would like to suggest the following question to the scientific community worldwide: Is psoriasin a potential mediator with properties to be involved in aggravation of already altered inflammation in the pathobiology of pulmonary hypertension? All experts and others interested in this field are welcome to reply and express their point of view and perspectives on this topic, in the next volume of PVRI Chronicle.

 

References

1. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nature reviews Cardiology 2011; 8: 443-455.

2. Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, Scheed A, Ritter C, Dahal BK, Vater A, Klussmann S, Ghofrani HA, Weissmann N, Klepetko W, Banat GA, Seeger W, Grimminger F, Schermuly RT. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. American journal of respiratory and critical care medicine 2012; 186: 897-908.

3. Pullamsetti SS, Savai R, Janssen W, Dahal BK, Seeger W, Grimminger F, Ghofrani HA, Weissmann N, Schermuly RT. Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 2011; 17: 7-14.

4. Kosanovic D, Dahal BK, Peters DM, Seimetz M, Wygrecka M, Hoffmann K, Antel J, Reiss I, Ghofrani HA, Weissmann N, Grimminger F, Seeger W, Schermuly RT. Histological characterization of mast cell chymase in patients with pulmonary hypertension and chronic obstructive pulmonary disease. Pulmonary circulation 2014; 4: 128-136.

 5. Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, Reiss I, Ghofrani HA, Weissmann N, Kuebler WM, Seeger W, Grimminger F, Schermuly RT. Involvement of mast cells in monocrotalineinduced pulmonary hypertension in rats. Respiratory research 2011; 12: 60.

6. Wolf R, Ruzicka T, Yuspa SH. Novel S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function. Amino acids 2011; 41: 789-796.

7. Madsen P, Rasmussen HH, Leffers H, Honore B, Dejgaard K, Olsen E, Kiil J, Walbum E, Andersen AH, Basse B, et al. Molecular cloning, occurrence, and expression of a novel partially secreted protein “psoriasin” that is highly up-regulated in psoriatic skin. The Journal of investigative dermatology 1991; 97: 701-712.

8. Webb M, Emberley ED, Lizardo M, Alowami S, Qing G, Alfia’ar A, Snell-Curtis LJ, Niu Y, Civetta A, Myal Y, Shiu R, Murphy LC, Watson PH. Expression analysis of the mouse S100A7/psoriasin gene in skin inflammation and mammary tumorigenesis. BMC cancer 2005; 5: 17.

9. Nasser MW, Qamri Z, Deol YS, Ravi J, Powell CA, Trikha P, Schwendener RA, Bai XF, Shilo K, Zou X, Leone G, Wolf R, Yuspa SH, Ganju RK. S100A7 enhances mammary tumorigenesis through upregulation of inflammatory pathways. Cancer research 2012; 72: 604-615.

10. Gauglitz GG, Bureik D, Zwicker S, Ruzicka T, Wolf R. The Antimicrobial Peptides Psoriasin (S100A7) and Koebnerisin (S100A15) Suppress Extracellular Matrix Production and Proliferation of Human Fibroblasts. Skin pharmacology and physiology 2014; 28: 115-123.

11. Itoh T, Nagaya N, Ishibashi-Ueda H, Kyotani S, Oya H, Sakamaki F, Kimura H, Nakanishi N. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology 2006; 11: 158-163.

12. Ikeda Y, Yonemitsu Y, Kataoka C, Kitamoto S, Yamaoka T, Nishida K, Takeshita A, Egashira K, Sueishi K. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. American journal of physiology Heart and circulatory physiology 2002; 283: H2021-2028.

13. Chelladurai P, Seeger W, Pullamsetti SS. Matrix metalloproteinases and their inhibitors in pulmonary hypertension. The European respiratory journal 2012; 40: 766-782.

14. Zheng Y, Niyonsaba F, Ushio H, Ikeda S, Nagaoka I, Okumura K, Ogawa H. Microbicidal protein psoriasin is a multifunctional modulator of neutrophil activation. Immunology 2008; 124: 357-367.

15. Furuya Y, Satoh T, Kuwana M. Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. International journal of rheumatology 2010; 2010: 720305.

16. Wang Q, Zuo XR, Wang YY, Xie WP, Wang H, Zhang M. Monocrotaline-induced pulmonary arterial hypertension is attenuated by TNF-alpha antagonists via the suppression of TNF-alpha expression and NF-kappaB pathway in rats. Vascular pharmacology 2013; 58: 71-77.

 17. Andresen E, Lange C, Strodthoff D, Goldmann T, Fischer N, Sahly H, Branscheid D, Heine H. S100A7/psoriasin expression in the human lung: unchanged in patients with COPD, but upregulated upon positive S. aureus detection. BMC pulmonary medicine 2011; 11: 10.

18. Shubbar E, Vegfors J, Carlstrom M, Petersson S, Enerback C. Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation. Breast cancer research and treatment 2012; 134: 71-80.

19. Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, Voelkel NF. Oxidative stress in severe pulmonary hypertension. American journal of respiratory and critical care medicine 2004; 169: 764-769.

 20. Veit F, Pak O, Egemnazarov B, Roth M, Kosanovic D, Seimetz M, Sommer N, Ghofrani HA, Seeger W, Grimminger F, Brandes RP, Schermuly RT, Weissmann N. Function of NADPH oxidase 1 in pulmonary arterial smooth muscle cells after monocrotaline-induced pulmonary vascular remodeling. Antioxidants & redox signaling 2013; 19: 2213-2231.

21. Sakao S, Tatsumi K, Voelkel NF. Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Respiratory research 2009; 10: 95.

Topics

Pathology and Pathophysiology
Pulmonary Hypertension

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PVRI Chronicle Vol 2: Issue 2 cover image

July 2015

PVRI Chronicle Vol 2: Issue 2

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