Inflammation and Hemorrhage/Coagulation in Primary Blast Lung Injury: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Peter Tang and Version 1 by xiangyan meng.

Primary blast lung injury (PBLI), caused by exposure to high-intensity pressure waves from explosions in war, terrorist attacks, industrial production, and life explosions, is associated with pulmonary parenchymal tissue injury and severe ventilation insufficiency. PBLI patients, characterized by diffused intra-alveolar destruction, including hemorrhage and inflammation, might deteriorate into acute respiratory distress syndrome (ARDS) with high mortality. 

  • blast injuries
  • acute lung injury
  • hemorrhage
  • inflammation
  • blood coagulation
  • therapeutics

1. Introduction

Primary blast injury results only from the direct impact of a shockwave on the body without injuries induced by debris, wall collapse, inhalation of toxic substances, and other causes. Shockwaves can damage all organs of the body, especially the air-containing organs such as the lungs, ears, nose, stomach, and intestines [1]. Primary blast lung injury (PBLI) is defined as “radiological and clinical evidence of acute lung injury (ALI) occurring within 12 h of exposure and not due to secondary or tertiary injury” [2]. Blast lung injuries are always characterized by the absence of external signs despite severe and often lethal internal injuries; therefore, they are frequently underestimated. In severe cases, PBLI can develop into ARDS and multiple organ dysfunction syndrome, which is potentially life-threatening [3].

2. Pathophysiological Performance of PBLI

The clinical manifestations of PBLI are similar to those of pneumonia and hemorrhagic pneumonia. The specific phases and pathological manifestations are shown in Table 1.
Table 1.
The phases, timing, and corresponding pathological manifestations of PBLI [1].

Phases and Timing

Main Pathological Manifestations of PBLI

Phase 1 [2]0–3 h

Pulmonary hemorrhage

  • The lung and blood vessels are compressed by the shockwave, forcing blood or air out through the alveolar septum or capillary walls, resulting in pulmonary hemorrhage

Phase 2 [3]4–24 h

Inflammation

  • Leukocyte infiltration and proinflammatory cytokine levels in the lungs are increased

  • The accumulation of MPO in the injured lung gradually increases in a time-dependent manner from 3 h through 24 h

Phase 3 [4]After 24 h

Hypercoagulation

  • Platelet thrombi and fibrin thrombi are formed

3. Crosstalk among Hemorrhage, Inflammation, and Coagulation

Inflammation and hemorrhage are the two main manifestations of PBLI, subsequently inducing a series of pathological and physiological changes, such as pulmonary edema, alveolar hemorrhage, and emphysema. The processes of inflammation and hemorrhage are not independent but are related to each other (Figure 1). Shockwaves destroy the pulmonary vascular structure directly and induce the activation of platelets, which are essential for maintaining hemostasis following mechanical injury to the vasculature. Meanwhile, inflammatory responses are triggered furtherly.
Figure 1. The main pathological manifestations in PBLI. The main pathological manifestations of PBLI are pulmonary hemorrhage, inflammation, and coagulation disorders. The shockwave caused rupture of the pulmonary capillaries, destruction of the alveoli, and entry of red blood cells into the alveolar space and interstitium. Inflammation is manifested by leukocyte infiltration and increased levels of proinflammatory cytokines in the lung. Coagulation disorders are characterized by the aggregation of activated platelets to form platelet thrombi and the gradual formation of fibrin thrombi. NETs: neutrophil extracellular traps.

3.1. Hemorrhage Promotes Inflammation in PBLI

The existing literature shows that shockwaves could induce platelet activation [23][5], expressing a variety of cell surface proteins involved in inflammation. It has been reported that P-selectin, an adhesion molecule present on activated platelets, promotes neutrophil–platelet, platelet–platelet, and monocyte–platelet interactions by binding to P-selectin glycoprotein ligand-1 (PSGL-1) on other cells [24,25][6][7].
Some studies have shown that soluble CD40L (sCD40L), as a platelet-derived microparticle, shed from the surface of activated platelets, is capable of activating leukocytes and endothelial cells [26,27][8][9]. Platelet-expressed CD40L interacts with CD40 expressed on endothelial cells, which causes numerous downstream effects, upregulating a number of proinflammatory mediators such as intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin [26][8].
Studies have confirmed that platelets express low levels of TLRs as pattern recognition receptors in the resting state; once activated, the expression of TLRs is upregulated, which triggers the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway to activate nuclear factor κB (NF-κB) and promote the release of inflammatory factors (TNF-α, IL-1, and IL-6), chemokines, and adhesion molecules (ICAM-1, VCAM-1, and ELAMs) [28,29][10][11]. Platelets express various TLRs, among which TLR4 plays a major role in inflammation. TLR4 has been shown to enhance platelet–neutrophil aggregations [30][12], and neutrophil extracellular trap (NET) formation in sepsis [30][12]. Wu et al. [31][13] observed that inhibition of the TLR4 signaling pathway could alleviate the pulmonary inflammatory response in ALI often caused by blunt chest trauma with hemorrhagic shock (THS). Thus, during the process of PBLI, wthe researchers posit that TLR4 and its ligands play important roles in the post-traumatic immune response and the development of inflammation in PBLI.
After blast injury, large numbers of hemoglobin-containing red blood cells leak into the alveoli, swallowed by macrophages in the alveoli, and heme is subsequently released from hemoglobin [32][14]. Free heme, as a metabolite after the rupture of red blood cells, can induce the proinflammatory response of macrophages. It can induce the production of reactive oxygen species (ROS) and NF-κB signaling molecules in macrophages, thereby promoting the release of inflammatory factors [33][15]. In Figure 2, wthe sresearchers summarize the probable pathway of hemorrhage promoting inflammation in PBLI.
Figure 2. Hemorrhage promotes inflammation in PBLI. Activated platelets express a variety of cell surface proteins such as CD40Ls, P-selectins, and TLRs to trigger inflammation responses. The p-selectin expressed by activated platelets mediates the binding of platelets to neutrophils. CD40L mediates the binding of platelets to endothelial cells and neutrophils. The expression of TLRs in platelets promotes binding with neutrophils. Upon binding, neutrophils, endothelial cells, and activated platelets initiate an inflammatory response that promotes the release of cytokines. The red blood cells that leak into the alveoli are swallowed by macrophages and release heme and globulin. Heme induces the release of ROS and activation of the NF-κB signaling pathway in macrophages, thereby triggering inflammation. CD40L: cluster of differentiation 40 ligand; NETs: neutrophil extracellular traps; TLR: Toll-like receptor; PI3K: phosphoinositide 3-kinase; NF-κB: nuclear factor kappa B; ROS: reactive oxygen species; IL-1: interleukin-1; IL-8: interleukin-8; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; CCL2: C–C motif chemokine ligand 2; VCAM-1: vascular cell adhesion molecule 1; ICAM-1: intercellular adhesion molecule 1.

3.2. Inflammation Aggravates Coagulation Disorders

The inflammatory response is a multifactorial defensive process of an organism to injury, such as infectious or noxious stimuli. During inflammation, cytokines modulate the coagulation system; therefore, in the study of inflammation, the involvement of the coagulation pathway must be taken into account. Therefore, it is speculated that inflammation is also crosslinked with coagulation during PBLI (Figure 3). These changes make the management of pulmonary hemorrhage after PBLI more complicated, which deserves further study.
Figure 3. Inflammation aggravates coagulation disorders in PBLI. During inflammation, inflammatory factors can promote thrombosis by regulating the coagulation system and fibrinolytic system. (A) Inflammatory factors promote platelet activation and aggregation to form platelet thrombosis. (B) Inflammatory factors cause the downregulation of antithrombin and protein C to inhibit fibrinolysis. (C,D) Inflammatory factors stimulate endothelial cells and monocytes to produce tissue factor, an activator of coagulation, resulting in fibrinous thrombi. (E) Neutrophils are activated by inflammatory factors to produce NETs, which promote coagulation by promoting the production of several coagulation factors. NETs: neutrophil extracellular traps; FXI: coagulation factor XI; FXII: coagulation factor XII.
Proinflammatory cytokines including interleukins and tumor necrosis factor (TNF) directly promote local coagulation, in addition to being responsible for regulating inflammatory responses [34][16]. A previous study [35][17] showed that the exposure of whole blood from healthy volunteers to IL-1β, IL-6, and interleukin-8 (IL-8) resulted in hyperactivation of platelets and increased clotting. In addition, TNF promotes platelet aggregation and activation. Several studies also confirmed that proinflammatory cytokines such as TNF-α, IL-1, and IL-6 play important roles in the initiation of coagulation [36,37,38,39][18][19][20][21]. In addition to promoting coagulation through the above pathways, proinflammatory cytokines also cause obstacles to the anticoagulant mechanism by inhibiting the activity of antithrombin (AT) and protein C [38][20].
TF is expressed on platelets, endotheliocytes, neutrophils, and eosinophils at organ and body surfaces. As the initiator of the extrinsic coagulation pathway, TF plays a central role in inflammation-induced coagulation initiation [40][22]. Normally, TF is hardly present in the circulating blood. However, in an inflammatory state, monocytes and endothelial cells can increase the expression of TF through proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 [36,41][18][23]. The TF expressed by monocytes and neutrophils promotes coagulation in turn.
After activation by cytokines or cytotoxins, neutrophils produce an extracellular fibrous network of DNA, histones, and granulins such as elastase to capture bacteria. This network of extracellular fibers is known as neutrophil extracellular traps (NETs). NETs have been reported to be associated with platelet aggregation and coagulation [42][24]. Fuchs et al. [42][24] discovered that NETs provide a scaffold and stimulus for platelet binding and aggregation. Histones in NETs or liberated after digestion of NET can also provide a stimulus for platelet aggregation. Cell-free DNA (cfDNA), as a component of NETs, promotes thrombosis by activating some proteases in the coagulation pathway, such as coagulation factors XII and XI, and suppresses fibrinolysis [43][25]. In ourthe previous study [9][26], wthe researchers found elevated expression of NETs in the lungs of mice with PBLI, which indicated an increased thrombotic risk in PBLI. After blast exposure, due to the overexpression of proinflammatory factors, TF, and NETs, local coagulation in lung tissue may result, which is contradictory to the pulmonary hemorrhage reaction, further complicating the treatment of PBLI.

4. Pharmacotherapy Principles for PBLI

At present, the clinical treatment of PBLI is mainly based on mechanical ventilation, intensive treatment, and supportive treatment. Pharmacotherapy methods that target different pathological manifestations of PBLI to stop bleeding, inhibit inflammation, and stabilize coagulation may be used to treat PBLI (Table 2).
Table 2.
Pharmacotherapies for primary blast lung injury.

Drug/Efficacy

Drug/Strategy

Protective Mechanism

Model

Author

Author

Country

Journal Year

References

Hemostasis

Recombinant activated factor VII (rFVIIa)

Coagulation factor, promotes the production of thrombin

BLI patients

Martinowitz et al.

Israel

2004

[44][27]

Tranexamic acid (TXA)

Anti-fibrinolytic agent, impairs fibrinolysis, inhibits clot decomposition

Adult trauma patients

Roberts

UK

2015

[45][28]

Fibrinogen γ-chain-coated adenosine 5′-diphosphate-encapsulated liposomes(H12-(ADP)-liposomes)

Targets the injured site, inhibits internal bleeding

BLI mice

Hagisawa et al.

Japan

2016

[46][29]

Thrombin@Fe3O4 nanoparticles

Targets the damaged site, promotes the coagulation cascade

-

-

-

-

-

Hemostatic dexamethasone nanoparticles (hDNP)

Targets the bleeding site, exerts anti-inflammatory effects

BLI rats

Hubbard et al.

US

2018

[47][30]

Anti-inflammation

Sivelestat sodium hydrate (sivelestat)

Reduces the expression of NE and IL-8

Severe burns rats

Xiao et al.

China

2016

[48][31]

Ulinastatin

Reduces the infiltration of inflammatory cells, reduces pulmonary edema and neutrophil infiltration, alleviates lung injury

Rats with severe burn–blast combined injury

Liu et al.

China

2018

[49][32]

BLI rabbits

Yuan et al.

China

2016

[50][33]

BLI rabbits

Dai et al.

China

2015

[51][34]

Perfluorocarbon (PFC)

Inhibits proinflammatory cytokine release and oxidative stress

BLI cells

Zhang et al.

China

2017

[52][35]

BLI canine

Zhang et al.

China

2020

[53][36]

N-Acetylcysteine amide (NACA)

Decreases myeloperoxidase activity, reduces NF-κB activation, attenuates lung inflammation

PBLI rats

Chavko et al.

US

2009

[54][37]

Anticoagulation

Heparin

Prevents diffuse intravascular coagulation, improves survival

Trauma patients and blast injury rats

Yang et al.

US

2022

[55][38]

rTFPI

Inhibits coagulation cascade

Gas explosion rats

Tian et al.

China

2020

[56][39]

References

  1. Smith, J.E.; Garner, J. Pathophysiology of primary blast injury. J. R. Army Med. Corps 2019, 165, 57–62.
  2. Scott, T.E.; Kirkman, E.; Haque, M.; Gibb, I.E.; Mahoney, P.; Hardman, J.G. Primary blast lung injury—A review. Br. J. Anaesth. 2017, 118, 311–316.
  3. Peng, L.H.; Guo, G.H. Advances in the research of blast lung injury. Zhonghua Shao Shang Za Zhi 2016, 32, 156–159.
  4. Ritenour, A.E.; Baskin, T.W. Primary blast injury: Update on diagnosis and treatment. Crit. Care Med. 2008, 36 (Suppl. S7), S311–S317.
  5. Valiyaveettil, M.; Alamneh, Y.; Wang, Y.; Arun, P.; Oguntayo, S.; Wei, Y.; Long, J.B.; Nambiar, M.P. Contribution of systemic factors in the pathophysiology of repeated blast-induced neurotrauma. Neurosci. Lett. 2013, 539, 1–6.
  6. Zarbock, A.; Polanowska-Grabowska, R.K.; Ley, K. Platelet-neutrophil-interactions: Linking hemostasis and inflammation. Blood Rev. 2007, 21, 99–111.
  7. Yang, J.; Furie, B.C.; Furie, B. The biology of P-selectin glycoprotein ligand-1: Its role as a selectin counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction. Thromb Haemost. 1999, 81, 1–7.
  8. Henn, V.; Slupsky, J.R.; Gräfe, M.; Anagnostopoulos, I.; Förster, R.; Müller-Berghaus, G.; Kroczek, R.A. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998, 391, 591–594.
  9. Hermann, A.; Rauch, B.H.; Braun, M.; Schrör, K.; Weber, A.A. Platelet CD40 ligand (CD40L)—Subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 2001, 12, 74–82.
  10. Blair, P.; Rex, S.; Vitseva, O.; Beaulieu, L.; Tanriverdi, K.; Chakrabarti, S.; Hayashi, C.; Genco, C.; Iafrati, M.; Freedman, J.E. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ. Res. 2009, 104, 346–354.
  11. Aslam, R.; Speck, E.R.; Kim, M.; Crow, A.R.; Bang, K.W.; Nestel, F.P.; Ni, H.; Lazarus, A.; Freedman, J.; Semple, J.W. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 2006, 107, 637–641.
  12. Clark, S.R.; Ma, A.C.; Tavener, S.A.; McDonald, B.; Goodarzi, Z.; Kelly, M.M.; Patel, K.D.; Chakrabarti, S.; McAvoy, E.; Sinclair, G.D.; et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 2007, 13, 463–469.
  13. Wu, X.J.; Liu, H.M.; Song, X.M.; Zhao, B.; Leng, Y.; Wang, E.Y.; Zhan, L.; Meng, Q.; Xia, Z. Penehyclidine hydrochloride inhibits TLR4 signaling and inflammation, and attenuates blunt chest trauma and hemorrhagic shock-induced acute lung injury in rats. Mol. Med. Rep. 2018, 17, 6327–6336.
  14. Saha, B.K. Idiopathic pulmonary hemosiderosis: A state of the art review. Respir. Med. 2021, 176, 106234.
  15. Simões, R.L.; Arruda, M.A.; Canetti, C.; Serezani, C.H.; Fierro, I.M.; Barja-Fidalgo, C. Proinflammatory responses of heme in alveolar macrophages: Repercussion in lung hemorrhagic episodes. Mediat. Inflamm. 2013, 2013, 946878.
  16. Theofilis, P.; Sagris, M.; Antonopoulos, A.S.; Oikonomou, E.; Tsioufis, C.; Tousoulis, D. Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19. Int. J. Mol. Sci. 2021, 22, 11170.
  17. Bester, J.; Pretorius, E. Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity. Sci. Rep. 2016, 6, 32188.
  18. Van der Poll, T.; Levi, M.; Hack, C.E.; Cate, H.; van Deventer, S.J.; Eerenberg, A.J.; De Groot, E.R.; Jansen, J.; Gallati, H.; Büller, H.R. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J. Exp. Med. 1994, 179, 1253–1259.
  19. Boermeester, M.A.; van Leeuwen, P.A.; Coyle, S.M.; Wolbink, G.J.; Hack, C.E.; Lowry, S.F. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch. Surg. 1995, 130, 739–748.
  20. Beaulieu, L.M.; Lin, E.; Mick, E.; Koupenova, M.; Weinberg, E.O.; Kramer, C.D.; Genco, C.A.; Tanriverdi, K.; Larson, M.G.; Benjamin, E.J.; et al. Interleukin 1 receptor 1 and interleukin 1β regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans. Arter. Thromb. Vasc. Biol. 2014, 34, 552–564.
  21. Eslamifar, Z.; Behzadifard, M.; Soleimani, M.; Behzadifard, S. Coagulation abnormalities in SARS-CoV-2 infection: Overexpression tissue factor. Thromb. J. 2020, 18, 38.
  22. Grover, S.P.; Mackman, N. Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis. Arter. Thromb. Vasc. Biol. 2018, 38, 709–725.
  23. Osterud, B.; Rao, L.V.; Olsen, J.O. Induction of tissue factor expression in whole blood: Lack of evidence for the presence of tissue factor expression in granulocytes. Thromb. Haemost. 2000, 83, 861–867.
  24. Fuchs, T.A.; Brill, A.; Duerschmied, D.; Schatzberg, D.; Monestier, M.; Myers, D.D., Jr.; Wrobleski, S.K.; Wakefield, T.W.; Hartwig, J.H.; Wagner, D.D. Extracellular DNA traps promote thrombosis. Proc. Natl. Acad. Sci. USA 2010, 107, 15880–15885.
  25. Gould, T.J.; Lysov, Z.; Liaw, P.C. Extracellular DNA and histones: Double-edged swords in immunothrombosis. J. Thromb. Haemost. 2015, 13 (Suppl. S1), S82–S91.
  26. Meng, X.Y.; Lu, Q.Y.; Zhang, J.F.; Li, J.F.; Shi, M.Y.; Huang, S.Y.; Yu, S.F.B.; Zhao, Y.M.; Fan, H.J. A Novel Animal Model of Primary Blast Lung Injury and Its Pathological Changes in Mice. J. Trauma Acute Care Surg. 2022, 93, 530–537.
  27. Martinowitz, U.; Zaarur, M.; Yaron, B.L.; Blumenfeld, A.; Martonovits, G. Treating traumatic bleeding in a combat setting: Possible role of recombinant activated factor VII. Mil. Med. 2004, 169 (Suppl. S12), 16–18.
  28. Roberts, I. Tranexamic acid in trauma: How should we use it? J. Thromb. Haemost. 2015, 13 (Suppl. S1), S195–S199.
  29. Hagisawa, K.; Kinoshita, M.; Miyawaki, H.; Sato, S.; Miyazaki, H.; Takeoka, S.; Suzuki, H.; Iwaya, K.M.; Seki, S.M.; Shono, S.M.; et al. Fibrinogen γ-Chain Peptide-Coated Adenosine 5′ Diphosphate-Encapsulated Liposomes Rescue Mice From Lethal Blast Lung Injury via Adenosine Signaling. Crit. Care Med. 2016, 44, e827–e837.
  30. Hubbard, W.B.; Lashof-Sullivan, M.; Greenberg, S.; Norris, C.; Eck, J.; Lavik, E.; VandeVord, P. Hemostatic nanoparticles increase survival, mitigate neuropathology and alleviate anxiety in a rodent blast trauma model. Sci. Rep. 2018, 8, 10622.
  31. Xiao, X.G.; Zu, H.G.; Li, Q.G.; Huang, P. Sivelestat sodium hydrate attenuates acute lung injury by decreasing systemic inflammation in a rat model of severe burns. Eur. Rev. Med. Pharm. Sci. 2016, 20, 528–536.
  32. Liu, W.; Chai, J. Influences of ulinastatin on acute lung injury and time phase changes of coagulation parameters in rats with burn-blast combined injuries. Chin. J. Burns 2018, 34, 32–39.
  33. Yuan, L.; Dai, Z.; Shi, Y.; Xu, A.; Zou, Z.; Lu, Z. The effect of ulinastatin on blood gas analysis in rabbits with acute lung injury following a blast. Chin. J. Emerg. Med. 2016, 25, 301–304.
  34. Dai, Z.; Yuan, L.; Zou, Z.; Lu, Z.; Shi, Y. Therapeutic effect of ulinastatin combined with dexamethasone on blast-induced acute lung injury in rabbits. Chin. J. Trauma 2015, 31, 461–466.
  35. Zhang, Z.; Liang, Z.; Li, H.; Li, C.; Yang, Z.; Li, Y.; She, D.; Cao, L.; Wang, W.; Liu, C.; et al. Perfluorocarbon reduces cell damage from blast injury by inhibiting signal paths of NF-κB, MAPK and Bcl-2/Bax signaling pathway in A549 cells. PLoS ONE 2017, 12, e0173884.
  36. Zhang, Z.; Li, H.; Liang, Z.; Li, C.; Yang, Z.; Li, Y.; Cao, L.; She, Y.; Wang, W.; Liu, C.; et al. Vaporized perfluorocarbon inhalation attenuates primary blast lung injury in canines by inhibiting mitogen-activated protein kinase/nuclear factor-κB activation and inducing nuclear factor, erythroid 2 like 2 pathway. Toxicol. Lett. 2019, 319, 49–57.
  37. Chavko, M.; Adeeb, S.; Ahlers, S.T.; McCarron, R.M. Attenuation of pulmonary inflammation after exposure to blast overpressure by N-acetylcysteine amide. Shock 2009, 32, 325–331.
  38. Yang, Z.; Simovic, M.O.; Edsall, P.R.; Liu, B.; Cancio, T.S.; Batchinsky, A.I.; Cancio, L.C.; Li, Y. HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma. Biomolecules 2022, 12, 101.
  39. Tian, L.Q.; Guo, Z.H.; Meng, W.Z.; Li, L.; Zhang, Y.; Yin, X.H.; Lai, F.; Li, Y.; Feng, L.; Shen, F.; et al. The abnormalities of coagulation and fibrinolysis in acute lung injury caused by gas explosion. Kaohsiung J. Med Sci. 2020, 36, 929–936.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback