Carbon monoxide, healing gas?

Wound healing activity of carbon monoxide liberated from CO-releasing molecule (CO-RM).

‘Wound microenvironment presents widespread oxidant stress, inflammation, and onslaught of apoptosis. Carbon monoxide (CO) exerts pleiotropic cellular effects by modulating intracellular signaling pathways which translate into cellular protection against oxidative stress, inflammation, and apoptosis. CO-releasing molecules (CO-RMs) deliver CO in a controlled manner without altering carboxyhemoglobin levels. This study observed a potential therapeutic value of CO in the wound healing by using tricarbonyldichlororuthenium (II) dimer (CO-releasing molecule (CO-RM)-2), as one of the novel CO-releasing agent. The effect of CO-RM-2 treatment was studied on wound contraction, glucosamine, hydroxyproline levels, and mRNA of cytokines/adhesion molecule in rats using a full-thickness cutaneous wound model and angiogenesis in chick chorioallantoic membrane (CAM) model. CO-RM-2 treatment increased cellular proliferation and collagen synthesis as evidenced by the increase in wound contraction and hydroxyproline and glucosamine contents. The mRNA expression of cytokines endorsed fast healing, as was indicated by the inhibition of pro-inflammatory adhesion molecules such as ICAM-1 and cytokine TNF-α and upregulation of anti-inflammatory cytokine IL-10. An ELISA assay of IL-10 and TNF-α cytokines revealed pro-healing modulation in excision wound by CO-RM-2 treatment. CO-RM significantly promoted the angiogenesis as compared to the iCO-RM group in vitro in CAM model demonstrating pro-angiogenic effects of CO-RM-2 in wound healing process. These results indicate that CO-RM-2 may have a potential application in the management of recalcitrant/obstinate wounds wherein, active wound healing is desired. This study also opens up a new area of research for the synthesis of novel CO-releasing molecules to be used for such purposes.’

Naunyn Schmiedebergs Arch Pharmacol. 2011 Jul;384(1):93-102. Ahanger AAPrawez SKumar DPrasad RAmarpalTandan SKKumar D. Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, Uttar Pradesh.

Carbon monoxide is a gas, forcing itself as an expansion to make tissue expand, yet not constrained by membranes the effect decreases at a distance from the origin of the molecular spreading effect. Since a gas forces a local zone to change shape, like the evolutionary reaction of scarring to pull tissue together in wound healing is now reduced when carbon dioxide is delivered to the wound healing site. Hence tensional/strain or tensegrity within the normal process from the scar is reduced. Such biological feats are huge, carbon monoxide changes the way the immune system works.

The tensegrity concept can be defined in terms of push and pull, where push is provided by struts and pull is provide by cables have a win-win relationship with each other. Pull is continuous and push is discontinuous. The two balance each other producing the integrity of tension and compression. Tensegrity structures consists only compression struts and tension cable members. These fundamental phenomena do not oppose, but rather complement each other. Tensegrity is the name for a synergy between a co-existing pairs of fundamental physical laws of push and pull, or compression and tension, or repulsion and attraction.

Thus a tensegrity is any balanced system composed of two elements, a continuous pull balanced by discontinuous push. When these two forces are in balance, a stabilized system results that is maximally strong “The tension-bearing members in these structures – whether Fuller’s domes or Snelson’s sculptures – map out the shortest paths between adjacent members (and are therefore, by definition, arranged geodesically) Tensional forces naturally transmit themselves over the shortest distance between two points, so the members of a tensegrity structure are precisely positioned to best withstand stress. For this reason, tensegrity structures offer a maximum amount of strength.”-  Donald Ingber

sourced from a pdf document entitled: Tensegrity based Poultry Shed miniproject report submitted by Nikhil Vyas supervised by Dr Suresh Bhalla, Department of Civil Engineeering, Indian Institute of Technology, Delhi April 2009.


CO prevents inflammatory responses via inhibition of NF-κB signaling pathway. (a) Inflammatory stimuli such as TNF-α and LPS lead to activation of ECs, which in turn activate inflammatory signaling cascades. The association between TLR4 and MyD88 inhibits IκB kinase activity, leading to NF-κB activation via p65/p50 nuclear translocation in TNF-α-stimulated ECs. CO significantly reduces TNF-α-induced Nox-mediated ROS generation, NF-κB activation and the expression of adhesion molecules such as ICAM-1, VCAM-1, and selectins. (b) Inflammatory stimuli induce (i) the recruitment of monocytes to the endothelium, thereby promoting their transmigration into the arterial intima, (ii) ECs apoptosis and (iii) VSMC proliferation. CO diminishes this inflammatory activation by reducing the expression of adhesion molecules, stimulating EC survival and inhibiting VSMC proliferation. Oxid Med Cell Longev. 2012; Regulation of ROS Production and Vascular Function by Carbon Monoxide 

If there is a symbiosis of intestinal bacteria to  maintain their residency within a host one of the potential methods of communication would be to use very ancient gases from a primitive atmosphere in abundance at that evolutionary time frame. Such an observation is entirely speculative on my part but the means that ancient bacteria could communicate is via carbon monoxide. So what exactly is carbon monoxide doing or accomplishing ?

“Exotic bacteria that do not rely on oxygen may have played an important role in determining the composition of Earth’s early atmosphere, according to a theory that University of Chicago researcher Albert Colman is testing in the scalding hot springs of a volcanic crater in Siberia.

He has found that bacteria at the site produce as well as consume carbon monoxide, a surprising twist that scientists must take into account as they attempt to reconstruct the evolution of Earth’s early atmosphere.

Colman, an assistant professor in geophysical sciences, joined an American-Russian team in 2005 working in the Uzon Caldera of eastern Siberia’s

Kamchatka Peninsula to study the microbiology and geochemistry of the region’s hot springs. Colman and his colleagues focused on anaerobic carboxydotrophs — microbes with a physiology as exotic as their name. They use carbon monoxide mostly for energy, but also as a source of carbon for the production of new cellular material.

This carbon monoxide based physiology results in the microbial production of hydrogen, a component of certain alternative fuels. The research team thus also sought to probe biotechnological applications for cleaning carbon monoxide from certain industrial waste gases and for biohydrogen production.

“We targeted geothermal fields,” Colman says, “believing that such environments would prove to be prime habitat for carboxydotrophs due to the venting of chemically reduced, or in other words, oxygen-free and methane-, hydrogen-, and carbon dioxide-rich volcanic gases in the springs.”

The team did discover a wide range of carboxydotrophs. Paradoxically, Colman found that much of the carbon monoxide at the Kamchatka site was not bubbling up with the volcanic gases; instead “it was being produced by the microbial community in these springs,” he says. His team began considering the implications of a strong microbial source of carbon monoxide, both in the local springs but also for the early Earth.

Earth’s early atmosphere contained hardly any oxygen but relatively large amounts of carbon dioxide and possibly methane, experts believe. Then during the so-called Great Oxidation Event about 2.3 to 2.5 billion years ago, oxygen levels in the atmosphere rose from vanishingly small amounts to modestly low concentrations.

“This important transition enabled a widespread diversification and proliferation of metabolic strategies and paved the way for a much later climb in oxygen to levels that were high enough to support animal life,” Colman says.

The processing of carbon monoxide by the microbial community could have influenced atmospheric chemistry and climate during the Archean, an interval of Earth’s history that preceded the Great Oxidation Event.

Previous computer simulations rely on a primitive biosphere as the sole means of removing near-surface carbon monoxide produced when the sun’s ultraviolet rays split carbon dioxide molecules. This theoretical sink in the biosphere would have prevented substantial accumulation of atmospheric carbon monoxide.

“But our work is showing that you can’t consider microbial communities as a one-way sink for carbon monoxide,” Colman says. The communities both produce and consume carbon monoxide. “It’s a dynamic cycle.”

Colman’s calculations suggest that carbon monoxide may have nearly reached percentage concentrations of 1 percent in the atmosphere, tens of thousands of times higher than current concentrations. This in turn would have exerted influence on concentration of atmospheric methane, a powerful greenhouse gas, with consequences for global temperatures.

Furthermore, such high carbon monoxide concentrations would have been toxic for many microorganisms, placing evolutionary pressure on the early biosphere.

“A much larger fraction of the microbial community would’ve been exposed to higher carbon monoxide concentrations and would’ve had to develop strategies for coping with the high concentrations because of their toxicity,” Colman says.

Colman and UChicago graduate student Bo He have conducted fieldwork in both Uzon and California’s Lassen Volcanic National Park. Colman has most recently journeyed to Kamchatka for additional fieldwork in 2007 and 2010.

“This fantastic field site has a wide variety of hot springs,” he says. “Different colors, temperatures, chemistries, different types of micro-organisms living in them. It’s a lot like Yellowstone in certain respects.” Lassen’s springs have a narrower range of acidic chemistries, yet microbial production of carbon monoxide appears to be widespread in both settings.

Collaborator Frank Robb of the University of Maryland, Baltimore, lauds Colman for his “boundless enthusiasm” and for his “meticulous preparation,” much-needed qualities to ensure the safe transport of delicate instruments into the field.

Some of the microbial life within the caldera’s complex hydrothermal system may survive in even more extreme settings than scientists have observed at the surface, Colman says. “One thing we really don’t know very well is the extent to which microbial communities beneath the surface influence what we see at the surface, but that’s possible as well,” Colman says. “We know from culturing deep-sea vent microbes that they can live at temperatures that exceed the temperatures we’re observing right at the surface, and some of the turn out to metabolize carbon monoxide.” ASTROBIOLOGY Magazine/NASA/University of Chicago Carbon Monoxide Bacteria and Earth’s Ancient Atmosphere

The National Science Foundation and the National Aeronautics and Space Administration’s Astrobiology Institute   have funded Colman’s Kamchatka research. The work offers insights into astrobiology, the study of the potential for life on other worlds, by showing how organisms might thrive in extreme environments beyond Earth, including the subsurface of Mars, Jupiter’s moon Europa, or even planets orbiting other stars.”

The authors summarize about potent biological gases like carbon monoxide (CO) and nitric oxide (NO), “… are complex, dynamic and adaptable. Numerous experiments have demonstrated that CO is involved in cellular adaptation to oxidative stress, and vascular dysfunction, leading to the maintenance of cellular and vascular homeostasis.” ‘Oxidative stress is an imbalance between the systemic manifestation of reactive oxygen species and a biological system’s ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals  that damage all components of the cell, including proteins, lipids and DNA.  Further, some reactive oxidative species act as cellular messengers in redox signalling.   Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signalling. ‘

Redox (reduction-oxidation) reactions include all chemical reactions  in which atoms have their oxidation state changed.

‘Redox reactions, or oxidation-reduction reactions, have a number of similarities to acid-base reactions . Like acid-base reactions , redox reactions are a matched set, that is, there cannot be an oxidation reaction without a reduction reaction happening simultaneously. The oxidation alone and the reduction alone are each called a half-reaction , because two half-reactions always occur together to form a whole reaction. When writing half-reactions, the gained or lost electrons are typically included explicitly in order that the half-reaction be balanced with respect to electric charge.

Though sufficient for many purposes, these descriptions are not precisely correct. Oxidation and reduction properly refer to a change in oxidation state  — the actual transfer of electrons may never occur. Thus, oxidation is better defined as an increase in oxidation state, and reduction as a decrease in oxidation state. In practice, the transfer of electrons will always cause a change in oxidation state, but there are many reactions that are classed as “redox” even though no electron transfer occurs (such as those involving covalent bonds). (Oxidation state is an indicator of the degree of oxidation of an atomin a chemical compound. The formal oxidation state is the hypothetical charge  that an atom would have if all bonds to atoms of different elements were 100% ionic. Oxidation states are typically represented by integers, which can be positive, negative, or zero. The increase in oxidation state of an atom through a chemical reaction is known as an oxidation; a decrease in oxidation state is known as a reduction . Such reactions involve the formal transfer of electrons, a net gain in electrons being a reduction and a net loss of electrons being an oxidation. For pure elements, the oxidation state is zero.’

Understanding How H-NOX (Heme Nitric Oxide/Oxygen) Domain Works
Needs First Clarifying How Diatomic Gases Are Relocated Inside This
Sensing Protein. A Molecular-Mechanics Approach
by Francesco Pietra

I hope I have not hit you with too many concepts here. Here is the rationale for this essay. The carbon monoxide gas has to get into  specific proteins, the query is how does it do this to create all these potential cellular changes that may promote healing improvement. So lets focus on this before any detail is introduced, make sense? If tensegrity is involved there has to be interaction within the shape itself of a particular molecule. here we go.

First the abstract: “H-NOX (Heme Nitric Oxide/Oxygen) domain has widespread occurrence, either standalone or associated with functional proteins, sending signals for functions that span from modulating vasodilation and neurotransmission with humans to competition and symbiosis with bacteria. Understanding how HNOX works, and possibly intervening on degeneration for health purposes, needs first clarifying how diatomic gases are relocated through this protein in relation to the deeply buried heme. To this end, a biased form of molecular dynamics, i.e., Random Acceleration Molecular Dynamics (RAMD), is used by applying a randomly oriented tiny force to heme-dissociated CO of Nostoc sp. H-NOX, while changing randomly the direction of the force, if CO travels less than specified for the evaluated block.The result is that a large area of the protein, comprising amino acids from serine 44 to leucine 67 along two adjacent helices, offers a broad portal to CO from the surrounding medium to the deeply buried heme. Most traffic is concentrated through a channel lined by tyrosine 49, valine 52, and leucine 67. This modifies the picture drawn from mapping Xe cavities on pressurizing Nostoc sp. H-NOX with Xe gas. What is the main pathway with Xe-cavity mapping becomes a minor pathway with RAMD, and vice versa. The reason is that the fluctuating protein under MD creates clefts for CO slipping through, as it is expected to occur in nature.”

So let me simplify does the gas diffuse into the heme center of the H-NOX molecule or does it follow a channel? There will be 4 figures from their simulation study trying to map the channel of entry and exit for the carbon monoxide molecule. Here is figure 1 from the report

Now Figure 2

Figure 3

Figure 4

“Conclusions. – This work has revealed that, by applying a randomly oriented tiny force – whose direction changes if CO travels by less than a tiny stretch in the evaluated block – to Fe-dissociated CO in Nostoc sp. H-NOX domain, egress of CO occurs from mainly a broad area. This is defined by the S44-G60 helix and a stretch (A63-L67) of the subsequent helix, both highlighted in hot pink in Fig. 1. Within this area, a channel lined by residues Y49, V52, and L67, highlighted in red in Figs. 1 and 4, is preferentially used by CO to cross the border.RAMD also identifies a secondary channel used by CO to travel from heme to outside the protein, through exit portal 1, lined by residues H12 and H16, highlighted in orange in Figs. 1 and 3. Mapping CO pathway through cavities filled by Xe-atoms, on pressurizing the protein with Xe gas, arrived at opposite conclusions as to the preferred path [12]. The two different views may be reconciled by taking into account that monitoring Xe cavities is a static procedure, while clefts through which the gas can travel are created by the protein fluctuations. RAMD is a dynamic procedure, one that makes CO capable of exploiting such clefts. In nature, translocation of diatomic gases through the H-NOX domain is a dynamic process.”

Here’s the summary for this essay. I asked the question about a gas carbon monoxide being able to improve healing. Some chemical reactions are seeing just that sort of response. I then mentioned almost in passing the tensegrity of shape sensing invoking the balance of push/pull going on within the detail of the architecture. This thought was followed by the evidence for early atmospheres giving rise with archibacteria using carbon monoxide as a kind of gas transmitter in ancient bacterial colonies as life slowly started to develop. Finally I show a very sophisticated Italian study by Francesco Pietra Accademia Lucchese di Scienze, Lettere e Arti, Classe di Scienze, Palazzo Ducale, IT-55100 Lucca. Basically they gently applied nano force and watched the molecule H-NOX stretch along the preferred entry and egress pathways for preferred transition of the carbon monoxide molecule to get into the center of the molecular shape, the critical term here is stretch/shape sensing along what they term the cleft. As carbon monoxide is used as a gas to accomplish transmitter interaction from a primitive atmosphere, a specific architecture of assembly was also required for the gas to interact with molecules built using a very specific rule set, by the rule set of assembly using the principles of tensegrity. To not only build the molecule but too dynamically move within the molecule changing shape along the way.


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Montreal Grandmother, Agnes Kent was saved by Raul Wallenberg from certain death, when he provided papers for her and her Mom to escape away from the Nazis. Today when asked what that escape meant, she replied,"Remind people, that while statesmen and whole countries remained silent and did nothing, a single individual chose to act, with ramifications that proved enormous. Similar choices confront us today. Write that simple truth she said, it can never be repeated often enough because the world keeps forgetting it."
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One Response to Carbon monoxide, healing gas?

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