COX-2 and the natural signaling pathways in resolution of acute lung injury.

The New Neander's Medical
Figure 1 Temporal events and programming in resolution of acute inflammation: the function of lipid-derived mediators. ‘Triggers’ such as microbial invaders, tissue injury and surgical trauma activate the release and formation of arachidonate-derived prostaglandins, which regulate early events in the inflammatory response. Initial chemoattractants recruit polymorphonuclear (PMN) cells that move by diapedesis from post-capillary venules, an event that is amplified by production of the 5-lipoxygenase pathway product leukotriene B4(LTB 4 ), a potent chemoattractant. During the progression of inflammatory events, plateletleukocyte interactions elicit the formation of lipoxins A 4and B 4 , which serve as ‘stop signals’ by blocking the further recruitment of polymorphonuclear cells from the post-capillary venules. This strategic location limits the number of neutrophils required for combating microbes and/or cleaning up tissue debris. At contained sites of inflammation, as exudates form and pustules are walled off, prostaglandins initiate many responses relevant in inflammatory events, but most notably they signal the end by activating the transcriptional regulation of 15-lipoxygenase (15-LO) in neutrophils, which in turn leads to the temporal dissociation and production of lipoxins from arachidonic acid, which have ‘pro-resolving’ and anti-inflammatory functions. Thisis referred to as class switching of the arachidonic acid–derived eicosanoids from prostaglandins and leukotrienes to lipoxins that initiate the termination sequence. This stop in further neutrophil entry into the exudate is also temporally associated with a switch of the families of lipid mediators generated from eicosanoids to resolvins of the E and D series as well as protectins (Fig. 2). Clock dials indicate set points for individual neutrophils as new neutrophils ‘parachute’ into exudates. COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; LT, leukotriene; LX, lipoxin. Source: Serhan and Savill, 2005.

Last update and review: July 16, 2020.

Contents hide
Short summary.
The key takeaways from Fukunaga et al., 2005 (1).
Inhibition of proinflammatory mediators has not proven effective in Acute lung injury (ALI).
A new investigative strategy emphasizes mediators promoting resolution from lung injury.
Disruption of cyclooxygenase 2 (COX-2) blocked resolution of ALI.
COX-2-derived proresolving lipid mediators lipoxin A4 (LXA4) and, in the presence of aspirin, 15-epi-LXA4, mediate anti-inflammatory actions.
Increased expression of LXA4 receptor (ALX) displayed dramatic protection from ALI.
These findings support a new approach to ALI and ARDS that emphasizes enhancing natural resolution signaling pathways.
Fukunaga et al., 2005 (1), on the natural signaling pathways in resolution of acute lung injury.
A picture gallery with images and figures from related articles (COVID-19, ARDS, invasive mechanical ventilation, inflammation).
Selected references:

Short summary.

Below, we share the Abstract and the Discussion parts of the article by Fukunaga et al., 2005 (1). The article explored a strategy in treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) that consists in emphasizing natural inflammation resolution signaling pathways.

Relevance: When you hear different bureaucrats and medical professionals say: “there is no treatment for COVID-19”, know that it is not true. The article by Fukunaga et al., 2005 (1), describes one of the possible strategies to address ALI and ARDS in COVID-19 and influenza pneumonia patients.

The key takeaways from Fukunaga et al., 2005 (1).

Inhibition of proinflammatory mediators has not proven effective in Acute lung injury (ALI).

A new investigative strategy emphasizes mediators promoting resolution from lung injury.

Disruption of cyclooxygenase 2 (COX-2) blocked resolution of ALI.

COX-2-derived proresolving lipid mediators lipoxin A4 (LXA4) and, in the presence of aspirin, 15-epi-LXA4, mediate anti-inflammatory actions.

Increased expression of LXA4 receptor (ALX) displayed dramatic protection from ALI.

These findings support a new approach to ALI and ARDS that emphasizes enhancing natural resolution signaling pathways.

Fukunaga et al., 2005 (1), on the natural signaling pathways in resolution of acute lung injury.

Abstract

Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. In its early exudative phase, neutrophil activation and accumulation in the lung lead to hypoxemia, widespread tissue damage, and respiratory failure. In clinical trials, inhibition of proinflammatory mediators has not proven effective. In this study, we pursued a new investigative strategy that emphasizes mediators promoting resolution from lung injury. A new spontaneously resolving experimental murine model of ALI from acid aspiration was developed to identify endogenous proresolving mechanisms. ALI increased cyclooxygenase 2 (COX-2) expression in murine lung. Selective pharmacologic inhibition or gene disruption of COX-2 blocked resolution of ALI. COX-2-derived products increased levels of the proresolving lipid mediators lipoxin A4 (LXA4) and, in the presence of aspirin, 15-epi-LXA4. Both LXA4 and 15-epi-LXA4 interact with the LXA4 receptor (ALX) to mediate anti-inflammatory actions. ALX expression was markedly induced by acid injury and transgenic mice with increased ALX expression displayed dramatic protection from ALI. Together, these findings indicate a protective role in ALI for COX-2-derived mediators, in part via enhanced lipoxin signaling, and carry potential therapeutic implications for this devastating clinical disorder.

Discussion.

Neutrophil recruitment and increased vascular permeability are hallmarks of ALI and ARDS. Our experimental model of ALI from acid aspiration recapitulated a mild form of this pathobiology with selective injury of the left lung limiting the severity of the injury and subsequent inflammation. This nonlethal injury enabled the animals to survive without mechanical ventilation, which can lead to additional ventilator-induced lung injury (25). Spontaneous resolution of ALI in this model facilitated identification of natural proresolving homeostatic mechanisms in the lung. Although lipid mediators derived from C20:4 are well appreciated to play pivotal roles in promoting the early inflammatory changes of ALI (7), evidence presented here indicates for the first time that select eicosanoids also promote recovery from lung injury.

Lung COX-2 expression and activity were significantly induced in our experimental model of ALI. Leukocyte COX-2 expression increases after acid aspiration (26) and during acute inflammation (27) and, in this study, acid injury also directly increased COX-2 expression in differentiated NHBE, suggesting contributions from multiple cell types to the increased COX-2 after ALI. Inhibition of COX-2 activity by pharmacologic or gene targeting decreased early PMN trafficking to the lung, but paradoxically led to dramatic increases in inflammation at later time points. A late, anti-inflammatory effect of COX-2, instead of the more widely appreciated early, proinflammatory action, was crucial to the timely recovery from ALI. Similarly, COX-2-catalyzed conversion of C20:4 to prostanoids has been identified as central to cardioprotection during ischemic preconditioning (28) and resolution of pleural inflammation (29, 30). COX-1-derived products may also have protective functions because its expression decreased after ALI, and deficiencies in COX-1 can exacerbate pulmonary inflammation in response to allergic and infectious stimuli (20, 31). Together these results indicate that the biosynthesis of COX products is temporally regulated in acute inflammation with early proinflammatory and, at least as important, late anti-inflammatory effects. These insights may help explain the failures of clinical trials that disrupted COX-derived product formation (9, 10).

In acute inflammation, COX-2-derived PGE2 induces leukocyte 15-lipoxygenase expression to establish biosynthetic circuits for anti-inflammatory lipid mediators, such as the LXs (12). After acid injury, COX-2 inhibition blocked the increased LXA4 production and resulted in an exacerbation of ALI with longer recovery times relative to animals with intact COX-2 function. ASA-acetylated COX-2 is still capable of enzymatic activity converting C20:4 to 15R-hydroxyeicosatetraenoic acid that can serve as a substrate for leukocyte 5-lipoxygenase-catalyzed conversion to 15-epi-LXs (16). In the presence of ASA, formation of 15-epi-LXA4 increased in the injured lung and, unlike selective COX-2 inhibition, ASA did not adversely impact recovery from ALI. Of note, COX-2-selective inhibitors can block the COX-2 active site serine from acetylation by ASA to inhibit the ASA-triggered 15R-hydroxyeicosatetraenoic generation (32), and concomitant administration of these two agents here resulted in an increase in the severity of ALI that was similar to that seen when animals received the COX-2-selective inhibitor alone. In addition to 15-epi-LXs, ASA-acetylated COX-2 can also catalyze the formation of resolvins, structurally distinct lipid mediators derived from docosahexaenoic and eicosapentaenoic acids that also display tissue-protective properties during acute inflammation (33, 34). Thus, the inhibition of prostanoid formation by ASA is countered by increased generation of ASA-triggered lipid mediators that can promote ALI resolution.

Both LXA4 and 15-epi-LXA4 interact with ALX to initiate an array of proresolving actions for leukocyte-epithelial cell interactions during inflammation. LXs regulate airway epithelial cell proliferation and block IL-8 release and PMN-epithelial cell transmigration (reviewed in Ref. 16). Experimental ALI and direct airway epithelial cell injury with acid induced ALX expression. Coupled with the dramatic protection from ALI afforded ALX-tg mice, these findings suggest ALX agonists as potential novel therapeutic agents for ALI.

In summary, our findings have uncovered a new role for COX-2-derived lipid mediators in promoting resolution of acid-initiated experimental ALI. Although multiple anti-inflammatory circuits likely exist, endogenous LX formation and ALX signaling appear capable of potent protection from acid-initiated ALI. Selective COX-2 inhibitors are widely prescribed as analgesics and anti-inflammatory agents. Similar to recent concerns regarding cardiotoxity (35), selective COX-2 inhibition may have additional detrimental consequences for recovery from lung injury. Our findings support a new approach to ALI and ARDS that emphasizes enhancing natural resolution signaling pathways.

Figure 1 Temporal events and programming in resolution of acute inflammation: the function of lipid-derived mediators. ‘Triggers’ such as microbial invaders, tissue injury and surgical trauma activate the release and formation of arachidonate-derived prostaglandins, which regulate early events in the inflammatory response. Initial chemoattractants recruit polymorphonuclear (PMN) cells that move by diapedesis from post-capillary venules, an event that is amplified by production of the 5-lipoxygenase pathway product leukotriene B4(LTB 4 ), a potent chemoattractant. During the progression of inflammatory events, plateletleukocyte interactions elicit the formation of lipoxins A 4and B 4 , which serve as ‘stop signals’ by blocking the further recruitment of polymorphonuclear cells from the post-capillary venules. This strategic location limits the number of neutrophils required for combating microbes and/or cleaning up tissue debris. At contained sites of inflammation, as exudates form and pustules are walled off, prostaglandins initiate many responses relevant in inflammatory events, but most notably they signal the end by activating the transcriptional regulation of 15-lipoxygenase (15-LO) in neutrophils, which in turn leads to the temporal dissociation and production of lipoxins from arachidonic acid, which have ‘pro-resolving’ and anti-inflammatory functions. Thisis referred to as class switching of the arachidonic acid–derived eicosanoids from prostaglandins and leukotrienes to lipoxins that initiate the termination sequence. This stop in further neutrophil entry into the exudate is also temporally associated with a switch of the families of lipid mediators generated from eicosanoids to resolvins of the E and D series as well as protectins (Fig. 2). Clock dials indicate set points for individual neutrophils as new neutrophils ‘parachute’ into exudates. COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; LT, leukotriene; LX, lipoxin. Source: Serhan and Savill, 2005.
Figure 1 Temporal events and programming in resolution of acute inflammation: the function of lipid-derived mediators. ‘Triggers’ such as microbial invaders, tissue injury and surgical trauma activate the release and formation of arachidonate-derived prostaglandins, which regulate early events in the inflammatory response. Initial chemoattractants recruit polymorphonuclear (PMN) cells that move by diapedesis from post-capillary venules, an event that is amplified by production of the 5-lipoxygenase pathway product leukotriene B4(LTB 4 ), a potent chemoattractant. During the progression of inflammatory events, plateletleukocyte interactions elicit the formation of lipoxins A 4and B 4 , which serve as ‘stop signals’ by blocking the further recruitment of polymorphonuclear cells from the post-capillary venules. This strategic location limits the number of neutrophils required for combating microbes and/or cleaning up tissue debris. At contained sites of inflammation, as exudates form and pustules are walled off, prostaglandins initiate many responses relevant in inflammatory events, but most notably they signal the end by activating the transcriptional regulation of 15-lipoxygenase (15-LO) in neutrophils, which in turn leads to the temporal dissociation and production of lipoxins from arachidonic acid, which have ‘pro-resolving’ and anti-inflammatory functions. Thisis referred to as class switching of the arachidonic acid–derived eicosanoids from prostaglandins and leukotrienes to lipoxins that initiate the termination sequence. This stop in further neutrophil entry into the exudate is also temporally associated with a switch of the families of lipid mediators generated from eicosanoids to resolvins of the E and D series as well as protectins (Fig. 2). Clock dials indicate set points for individual neutrophils as new neutrophils ‘parachute’ into exudates. COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; LT, leukotriene; LX, lipoxin. Source: Serhan and Savill, 2005.

A picture gallery with images and figures from related articles (COVID-19, ARDS, invasive mechanical ventilation, inflammation).

Dystopia: A video interview with an undercover nurse who worked in a New York hospital during the COVID-19 outbreak. By the early May 2020, Elmhurst doctors were killing 100% of their COVID-19 patients on mechanical ventilation. Many were intubated inappropriately.
Dystopia: A video interview with an undercover nurse who worked in a New York hospital during the COVID-19 outbreak. By the early May 2020, Elmhurst doctors were killing 100% of their COVID-19 patients on mechanical ventilation. Many were intubated inappropriately.
A dummy with a ventilator. Are you prepared to deal with COVID-19?
Principles And Practice of Mechanical Ventilation, Third Edition (Tobin, Principles and Practice of Mechanical Ventilation) by Martin J. Tobin.
Current understanding of immunology of vaccines containing alum adjuvants in vivo. Alum immunization leads to recruitment of neutrophil, natural killer cell, macrophage, eosinophil, and immature DC at the injection site. Immature DCs take up soluble Ag released from alum or particulate Ags mixed in alum in the subcutaneous areas and migrate towards draining lymph node (DLN). Soluble Ag can reach to DLN without help of DCs. In T cell area (paracortex), soluble Ags leaked out of conduits are taken up by resident DCs. DCs present Ag to the naïve T cells or transfer Ag to the resident DCs that present Ag to those T cells. In addition, B cells are capable of binding to this Ag with their surface immunoglobulins. B cells undergo activation, produce effector B cells (eB cells), and rapidly differentiate in plasma cells (PCs). Plasma cells produce low-affinity antibodies (LAb). B cells also migrate to B cell follicle. On the other hand, as a result of CD8 and CD4 T cell activation, effector CD8 (eCD8) T cells and effector CD4 (eCD4) T cells are produced. The eCD4 polarizes into T helper (Th) 1, 2, 17 or T follicular helper (Tfh) cells though alum induces development of mostly Th2 and Tfh cells. Tfh or Th2 may reach to the border of B cell follicle to activate B cells that produce eB cells and then PCs. The PCs consequently produce and secrete high-affinity antibody (HAb). Few alum-fed DCs and eCD4 may travel to efferent lymph vessels to reach into the distant LN in vivo. Ag: antigen, HEV: high endothelial venule, PVS: perivenular space (see text for explanation). Source: Ghimire, 2015.
"The next maneuver is proning the patient, or placing them in the proned position, to improve oxygenation to the posterior lungs (In ARDS on mechanical ventilation)." Source: Mechanical ventilation in emergency medicine (book) by S. R. Wilcox, 2019.
An ICU doctor from Italy Marco Garrone, who is one of the study (1) authors, honestly admits: "We started with "intubate as fast as you can".
Fig. 1.Placement of the index finger (gently, barely touching) on the body of the sternomastoid muscle to judge the presence of phasic contraction and qualitatively determine its magnitude(mild, moderate, marked). Source: Tobin, 2019.
Michael J. Tobin: "Watching breathing pattern surreptitiously in order to evade the cofounding influence of the Heisenberg principle, wherein the technique of measurement changes the very entity being measured." Source: Tobin, 2019.
Fig. 2. Model of immunopathological events associated with SARS clinical evolution. SARS patients mount robust IFN-mediated innate immune responses during early (acute) illness and peak symptomology. Following the median SO2 nadir in surviving patients (late SARS), most SARS patients resolve inflammation and mount effective adaptive immunity against SARS CoV. Immune dysregulation in severe SARS patients is hallmarked by continued expression of inflammatory chemokines and ISGs and deficiencies in MHC and Ig gene expression. Immune-mediated pathology worsens in the minority of susceptible SARS patients and unresolved CXCL10 expression and viral burden is associated with poor outcome. Source: Cameron, 2007.
Figure 1Information flow in the early stages following mild trauma with infection. Each cell commits to recruit and activate others based on multiple inputs, generally requiring evidence of both injury and infection, before it joins fully in amplifying the inflammatory process. Not shown are interactions among leukocytes, endothelium, platelets and coagulation factors; the generation of stop signals; and the flow of information over subsequent days, including the transition to wound healing (see text). Source: Nathan, 2002.
Figure 4 |Three modes of adaptation and maintenance of tissue homeostasis. The state of a tissue can range from basal, to stressed or malfunctioning, to damaged or infected, and each state is graded (as indicated by shading). The state affects the mode of maintenance of tissue homeostasis or adaptive responsethat is engaged by tissue-resident macrophages and, in some tissues, by other types of leukocyte. Blue arrows indicate signals that report the tissue state to macrophages; red arrows indicate macrophage-derived signals thatcontrol tissue adaptation. At one extreme of the range of responses is inflammation, which follows infection or tissue damage. By contrast, tissue stress or malfunction induces parainflammation, which helps a tissue to adapt to the noxious conditions and restore tissue functionality. Dysregulated para-inflammation might be responsible for the chronic inflammatory states that are associated with many modern human diseases, such as type 2 diabetes and atherosclerosis. Source: Medzhitov, 2008.
Figure 2 |The inflammatory pathway. a, A generic inflammatory pathway consists of inducers, sensors, mediators and effectors. Table 1 provides examples of each component for several inflammatory pathways. b, Inducers of inflammation can be classified as exogenous or endogenous, and these two groups can be further classified as shown. ECM, extracellular matrix; PAMP, pathogen-associated molecular pattern. Source: Medzhitov, 2008.
Figure 1 |Causes, and physiological and pathological outcomes, of inflammation. Depending on the trigger, the inflammatory response has a different physiological purpose and pathological consequences. Of the three possible initiating stimuli, only infectioninduced inflammation is coupled with the induction of an immune response. Source: Medzhitov, 2008.

Selected references:

1. Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD. Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol. 2005;174(8):5033-5039. doi:10.4049/jimmunol.174.8.5033

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