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– In this article, I'm going to share with you eight red-flag signs of narcissistic abuse. So be sure to stick around until the end of the article, because I've got a lot of good stuff for you today. Let's get started.
Now, the first thing I want to say is it's important to remember that these red flags can show up in any relationship, not just our romantic lives. But they can show up with so-called friends, as well as romantic interests. They can show up at work with colleagues, and bosses. They can show up with neighbors. They can show up with family and in-laws. It doesn't matter. They can show up in any area of your life, any relationship.
The important thing, however, is that you pay attention and tell yourself the truth about what it is that you are seeing, hearing, feeling, what you are experiencing. You know what you live, trust yourself.
So let's talk about eight red-flag signs of narcissistic abuse.
Number 1: Love bombing.
Now, first on the list of eight red-flag signs of narcissistic abuse is a love bombing. It all starts here. You'll find yourself on the receiving end of intense admiration, adulation, attention, and praise. So much so, it's actually awkward and uncomfortable at times. Unless, of course, you are a love addict. Then it's like love. And you're in real trouble because this will soon be followed by devaluation. And sometimes even, especially if they think that they can get away with it, verbal abuse in the way of criticism, blaming, shaming, name-calling, that sort of thing.
Number 2: Gaslighting.
Number two on the list of red flags of narcissistic abuse is gaslighting, which fundamentally boils down to another person working to cause you to doubt yourself as well as your memory and your perceptions of reality. So let me put it to you this way, If you're in a situation where you're feeling like you have to start recording your conversations, in order to prove to yourself and maybe others as well that you are in fact not crazy, not a liar, or a delusional whack job, you're at the very least in an unhealthy relationship. And it's highly likely that you're being narcissistically abused. If you want to learn more about gaslighting, you can check out this article here.
Number 3: Intentionally sabotaging your relationship with others.
Now, this will usually be done behind your back, certainly, you know, because narcissists are sneaky, manipulative, little cowards to their core. But what it is is they'll work real hard to manipulate the perceptions of others, to poison the hearts and minds of others towards you, planting little seeds about your faults, and your flaws, and your transgressions, so-called transgressions more often than not, but your shortcomings and your inferiority.
They'll do this passively or outright, directly, making up lies, spinning truths, lying by omission, whatever it takes to, again, manipulate the perception of others and poison the hearts and minds of them towards you. They'll gossip about all the things you've supposedly done and not done. And they'll go as far as making up complete fiction to manipulate how others perceive you, to poison how others perceive you, including the perception of children towards you, if they think they can get away with it. That's how insecure and sick narcissists can be.
Number 4: You're bad, wrong, or crazy.
Making you out to be bad, wrong, or crazy for having legitimate feelings and emotional responses to appalling and fully crazy-making attitudes and behavior. Here's how this works:
Step one: They behave inappropriately, appallingly, and often even cruelly.
Step two: You being a human being with a heart and feelings, you have a legitimate emotional reaction or response, a feeling response to the appalling, often cruel attitudes and behavior, to the inappropriate, appalling, and cruel attitudes and behavior. You have a feeling about that.
Step three: They blame, shame, and criticize you for having a legitimate feeling response, feeling reaction to the appalling attitudes and behavior, to the fully insane crazy-making situation that you find yourself in. You get blamed for it—sick stuff.
Number 5: Lying to avoid responsibility.
Now, this shows up in the way of blame-shifting and putting words in your mouth, saying that you've done and said things that you both know you've never actually done or said—a big red flag. And for me personally, this is an absolute non-negotiable deal breaker in any relationship. Now here's the thing, Narcissists will say whatever it takes, whatever tall tale no matter how untrue, cruel, or bizarre. Just like the toddler who got caught with their hand in the cookie jar when they'd been told countless times that they can't have a cookie.
This is what you're dealing with, an emotional toddler. And they'll go to any lengths, say whatever it takes to prove their point, win the right fight, or avoid accountability and responsibility. This is what you're dealing with. When you see this happen, this is not time to be second-guessing yourself. This is the time to be telling yourself the truth about what you are seeing, hearing, and feeling. How many times have you been through this cycle with this individual? And God forbid, you're making sense, you have proof, or they've backed themselves into a corner.
You can also expect this to go to the next level if they've managed to trigger themselves, which they often do. We don't even need to trigger them. They'll trigger themselves, their own insecurities, inferiority complex, and inadequacy. When that happens, when the mask slips, you can expect this whole thing to go to the next level. Again, they'll be willing to say whatever it takes, lie by omission, twist, distort, leaving huge chunks of the truth. They'll do and say whatever it takes to prop themselves up like the insecure, weak cowards that they actually are.
Number 6: You're dealing with a hero or a victim.
You are dealing with a hero or a victim, but never ever a villain, not even someone who's ever made a mistake. In other words, never being at fault or responsible for any issue in the relationship. No matter what has gone on you, somehow, are always to blame. Why? Because these people are masters of the blame-shifting game.
And if this is happening to you, you are for sure being narcissistically abused. Absolutely, without question. And it's important that you learn to hold onto yourself, do what you need to do to get and stay clear, hold onto your truth, hold onto your reality, and then make your decisions from there.
Number 7: Showing little to no genuine interest in who you are as a person.
Now, with the exception, of course, to when this actually might serve them in any way, then they'll pay attention. Then suddenly they're interested in who you are as a person. But generally speaking, you'll notice there's actually a lack of sincere, genuine interest in who you really are as a person. Again, unless it serves them. Or if they're on a fact-finding mission, gathering data that they'll be able to use later.
And you'll know the difference. You can feel the difference between someone who's meeting you heart to heart and has a genuine interest in getting to know you and wants to know about you. Where are you at in your life? What's going on? What's exciting? What's new? How's your heart, right? You can feel that. And you can feel when someone is feigning interest for manipulative purposes because it serves them in some way. Or they're just gathering data so that they can potentially use it later.
You feel the difference because actually if you're paying attention, feeling into your body, you're in touch with what you're feeling, that will actually give you the heebie-jeebies. You'll get the yuck factor. You'll feel it on some level.
Number 8: You're dealing with an entitled childish ingrate.
Entitled to your time, your energy, your attention. Entitled to all your resources, financial and otherwise, your home, car, belongings, et cetera. Entitled to behave any way they choose anytime they want, and you don't get to have a thought, an opinion, or a feeling about it. When dealing with someone who feels entitled to behave any way they choose without being called out on it ever. When dealing with someone who feels entitled to target whomever they choose, including a child or a minor without being called out on it ever.
When you're dealing with someone who feels entitled to just come and go as they please, irrespective of agreements, obligations, responsibilities, boundaries, etc., without being called out on it ever. In other words, they feel entitled to commit often the worst possible relationship crimes without being called out on it ever. How dare you have an opinion, a thought, a feeling about their sense of entitlement and all the relationship crimes they commit in the relationship. How dare you have an opinion or a feeling about that? Don't you know who they think they are?
If this is the situation you find yourself in, if this is what you are dealing with, someone who lives from this place of entitlement, you, my friend, are being narcissistically abused.
Read More: 5 Prices You Must Pay If You Stay with a Narcissist.
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France issues coronavirus warning after country sees huge drop in COVID-19 deaths
THE sharp drop in France's coronavirus death toll should not be a reason for complacency, the president of the scientific council advising the French government on the epidemic warned on Sunday.
French health officials reported a big fall in the country's coronavirus death toll on Sunday, with 242 deaths in 24 hours, a drop of more than a third on the previous day. "The virus will continue to circulate for months and collective immunity will remain low," Professor Jean-François Delfraissy told French newspaper Le Monde in an interview.
"Today, our enemy is invisible," he continued, as he said that "anyone displaying even mild symptoms" should be systematically tested in a bid to prevent a second wave of infections.
French health officials said last week that less than 10 percent of the population in France had been infected with the virus, noting this meant there was going to be no herd immunity by the time the lockdown is lifted next month.
The number of hospital deaths – 152 – was the lowest daily toll in five weeks, while 90 people died in nursing and care homes.
The epidemic has now claimed 22,856 lives in the country since the beginning of March, health chief Jerome Salomon told a daily press briefing.
While the number of deaths from the virus has risen, the rate at which casualties have mounted has steadily fallen over the last two weeks.
In addition, the number of people in a serious condition needing life support dropped for the 18th consecutive day.
The virtual lockdown ordered by President Emmanuel Macron to slow the spread of the virus has been in place since March 17 and is due to be lifted on May 11. S
schools and some shops will gradually reopen, though cafés, cinemas, restaurants and hotels will remain closed.
Prime Minister Edouard Philippe is due to present the government's plan to unwind the confinement to parliament on Tuesday, and politicians will then vote on the measures.
M Philippe said in a Twitter post on Sunday that the government's lockdown exit plan would focus on six key areas: public health, schools, businesses, public transport and public gatherings.
Officials are also debating whether or not to proceed with a smartphone application that could warn users if they came into contact with a coronavirus carrier, though the move has raised questions about the impact of tracing technology on civil liberties.
Nearly three million people have been infected by the novel coronavirus globally and over 205,000 have died since it was first detected in central China late last year, according to a Reuters tally.
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The Boston Bruins, spearheaded by Brad Marchand and David Pastrnak, are prepared to take the ice against Taylor Hall, Kyle Palmieri, and the New Jersey Devils at the Prudential Center in an Eastern Conference tilt. The opening faceoff will be at 7 p.m. ET on Tuesday, November 19, and it can be caught live on New England Sports Network.
Boston Bruins vs. New Jersey Devils Odds
Boston is 12-8 straight up (SU) and has earned moneyline bettors 0.4 units this season. Through 20 regular season contests, 10 of its games have gone over the total, while eight have gone under and just two have pushed. This 2019-20 Bruins team is 5-4 SU on the road.
Boston has converted on 28.1 percent of its power play chances this year, a figure that places them in the top-5 among NHL teams. Additionally, its penalty kill is ranked 11th overall, and it's successfully killed off 83.6 percent of its penalties..
With a .927 save percentage and 27.6 saves per game, Tuukka Rask (8-4-2) has been the top option in goal for Boston this year. If Boston decides to rest him, however, they may turn to Jaroslav Halak (4-4-3), who has a .924 save percentage and 2.56 goals against average this year.
New Jersey is 7-12 straight up (SU) and has lost 5.3 units for moneyline bettors this year. 11 of its games have gone over the total, while eight have gone under and none have pushed. It's 3-7 SU as the home team this year.
The Devils have converted on just 14.3 percent of their power play opportunities this season, a figure that's ranked 24th in the NHL. On the other hand, its penalty kill is ranked 22nd overall, and it's successfully killed off 76.1 percent of all opponent power plays.
MacKenzie Blackwood (25.6 saves per game) has been the top netminder in goal for the Devils. Blackwood has seven wins, seven losses, and three OT losses to his name and has maintained a pedestrian 2.79 goals against average and a subpar .904 save percentage this season.
Boston Bruins vs. New Jersey Devils Free Picks
Pick: SU Winner – Devils
Betting Trends
The Devils are 1-3 in games decided by shootout. The Bruins are 0-4 in shootouts.
The total has gone under in four of New Jersey's last five outings.
Six of Boston's last ten games have been decided by two goals or more. The team is 5-1 in those games.
Boston skaters have given out the ninth-most hits in the league (23.9 per game).


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Understandably, Asian brides are not for sale, hence men cannot buy a woman from a second nation who shows their self on a internet dating site. The fable that anyone can purchase a bride is likely to be considered one of the most typical types. Everything you will be in a position to do is usually put money into dating providers or perhaps other email order woman websites. There are many relationship tools where you can speak to any Cookware girl you will need. They provide you with straightforward instruments, just like messenger and video conversation.
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In 2010, there initially were about 4, 000 overseas mail buy brides in the US. Asian countries similar to China and tiawan, Japan, Vietnam, etc ., also provide an abundance of stunning and qualified girls who all dream of assemblage Western bachelor. A distinctive feature of any kind of Asian all mail order star of the wedding is her loyalty. The Asian region tradition stances a person as your head of the home, so a wife at all times helps her husband's choices and does her best to build a heat area at house. Once you communicate with women for a enough amount of time and know that your sweetheart likes you, move to significant actions.
And it might permit women in some fairly horrendous situations management with their future. Nonetheless there are on top of that stories of abuse or perhaps scamming, coming from each side on the transaction. In terms of age, 20% are years of age, forty an individual % happen to be 21-25, twenty-four % happen to be 26-30, 10 percent 31-35, and just 4 p. c over the age of 35. Yes, each step to look for a bride web based is legal and moral in Western international locations. Most of those ladies fantastic in search of the good associate, and they don't care into the monetary circumstance or capacity to offer to a family event.
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Planing a trip to another region could be high-priced and time consuming. With snail mail order birdes-to-be, males can save whenever and cash by appointment their potential companions on the internet. Online group meetings permit couples to get to know the other person better prior to they make virtually any selections regarding marriage. To comprehend how these platforms function, it is necessary to simplify what's a deliver order bride.
Oriental Wives Require a Break Using their Traditions
At times such excursions are cheaper than if a traveler just catalogs the resort and buys tickets, which can be pretty shady. The variety of K-1 visa individuals from Asia, Europe, South America, and North America in 2019, was circular 23, five-hundred. Not all of them had been submit order brides to be, but many mail purchase brides right from these areas apply for this kind of very visa to marry their American husbands. In 2020, all of the applicants reduced to 14, 700, which in turn, nonetheless, is normally defined by COVID limitations. There are fewer mail order brides in these countries, yet men get married to these ladies as a result of they are no let alone engaging and still have an similar mindset. Inspite of these statistics, folks have a very large mistrust for these suppliers.
Tendencies and childhood Asian females are homier, more family-oriented, and obedient containing nothing to carry out with western ladies. The last ones need to construct a profitable job, have a rebellious heart, and often prefer feministic improvements as well as do hurry to commit their time to as well as elevating kids. Millions of Asian brides dream of marrying international guys and leaving with regard to their homelands. A great acute shortage of Oriental suitors or perhaps personal causes? Here are the commonest explanation why Oriental women are so desperate to marry Americans. mail wife ❌ Avoid web sites with low-effort and non-validated single profiles. That's the vital thing to take notice to—low-quality dating profiles with odd self-descriptions, some photographs, and no helpful info, in fact , are good causes to travel the platform.
If you're completely certain you wish to see her once more, take the first step. Relationship experts also suggest that you merely get in touch along with her instantly following your date and say thanks. This could even speedily remove useless waiting events or misunderstandings. In order to make a romantic relationship work, you need to at all times esteem her tastes and pursuits. And extra importantly, you shouldn't make-believe that you like a similar things your companion favors.
Several websites are devoted to assisting you to meet the perfect match. Some have been successful and have made a long-lasting romance from their earliest assembly. Ukraine and Spain, are a pair of one of the best areas to obtain mail buy brides right from. Western men such as the look and characteristics of Slavic women.


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World Wetlands Day: A call to acknowledge our wetland ambassadors
Wetlands, a lifeline to our necessities and threatened wildlife, account for nearly half of Bangladesh. The Business Standard Earth today features an array of threatened species that can be guardians of wetlands of every kind
I am a 90s kid, born and raised in Dhaka. I am an eyewitness to how, over the years, the horizonless wetlands of Banasree and Aftabnagar were turned into a concrete jungle.
I, being a field biologist, know how the metropolis is still expanding in every direction, engulfing one wetland after another. This is the habit of all the fast-growing cities of Bangladesh.
This is the sad saga of our wetlands, which are being filled up and sold as residential plots, poisoned and converted for farming, and forgotten and destroyed at an unprecedented rate.
Today is World Wetlands Day and it calls for Wetlands Action for People and Nature. In despair, I looked at the map. From the haor basins of the northeast to the southern mangroves, to the riparian systems of the Hill Tracts to oxbow lakes and wetland depressions of central and western Bangladesh, I saw wetlands everywhere. I saw numerous blue areas of all sizes and shapes that are holding this riverine country together.
I noticed the Sundarbans and the Tanguar Haor for they are the Ramsar sites, wetlands of international importance under the Ramsar Convention, which is an intergovernmental environmental treaty established in 1971 by Unesco that had eventually led to this yearly observation.
I noted the Marjat Baor, Chalan Beel, Hakaluki and a few other locally recognised protected wetlands. But more than 90% are unprotected and left to their fate. I saw no umbrella species, conservation of which means conservation of the wetlands.
The Business Standard Earth, today, features an array of threatened species that can be guardians of wetlands of every kind. These extraordinary wildlife can restore our severed relationship with wetlands.
A cat in love with water
Fishing cats live in almost all wetlands of Bangladesh. Weighing a maximum of 15kg, these small cats are slightly bigger than a domestic pussycat with a robust palate for a fish-dominated diet.
The rapid destruction of wetlands and being in continuous conflict with humans has forced this feline to a severe extinction crisis. These cats live at the top of the wetland food chain and saving them will save the wetlands.
A beauty queen
The queen loach is undoubtedly the most beautiful fish living in our wetlands. This small fish with yellow vertical stripes on a greenish-black base is mostly concentrated in the Chalan Beel and other haor areas. Although a delicacy, other than during monsoon, the fish is very rarely caught. It is endangered in Bangladesh, and dependent on pristine water quality. This beauty queen can be treated as an ideal ecological indicator.
A ruler of the haors
Our haor basin of northeastern Bangladesh is the breeding ground of the massive and majestic Pallas's fish eagle. Every year in winter, this bird visits its natal place far from the northern hemisphere. It raises its chick, then starts for the cyclic return journey. A study published last year in Oryx counted 53 breeding pairs in haors.
This is a globally endangered raptor, which means less than 2,500 of them survive on the earth. The eagle can be the banner of our haor conservation scheme.
A stream guardian
The recently discovered short-clawed otters by a team of scientists from the University of Dhaka usher in hope for the forest streams. Up until last year, these otters had been completely unheard of.
It has now been found that these globally vulnerable otters live in good numbers in almost every stream-fed forest of Moulvibazar, Habiganj and the Hill Tracts. These otters are ideal keystone species to protect these riparian ecosystems.
An underwater king
The humped featherback or chital is a predatory indigenous fish. It can attain a huge size, sits atop the underwater food web and is commercially harvested. Its status is fast deteriorating, now marked as near threatened. The Chalan Beel, one of its refuges, has shrunk 98% in the last 30 years under the brunt of human-induced pressure.
Putting the species at the frontline can restore a sustainable fishing practice at the wetlands.
A mangrove spirit
The creeks of the Sundarbans are home to one of the world's most elusive birds, the masked finfoot. The forest supports an isolated population, which is very likely one of the two breeding populations in the world.
Increase in salinity, overfishing, poison fishing and poaching are the reasons behind its demise. A 2020 study published in Forktail deemed it as the 'next avian extinction in Asia' and suggested further downgrading of its status as critically endangered.
Measures to save this bird are urgent, success in which can globally exemplify our marshy mangroves.
A tune of the flooded grasslands
The bristled grassbird is a master of music and a roamer of dense and tall grasslands. It is a very little known bird. There are only a handful of recorded sightings from the meadows of the haor basin and the seasonally flooded grasslands of the Ganges-Brahmaputra River.
This bird is globally vulnerable, meaning its heavenly tune is getting fainter every day. This is an ideal candidate to save the seasonal grasslands, an even further ignored wetland habitat.
A peacock with a shell
In Hindu mythology, it is said that our world lies on the back of a giant turtle. That way, the fate of our wetlands lies on the back of the peacock softshell turtle.
Named for having four eyespots on the back resembling those of the peacock, this elegant species is globally endangered. The turtle is reported from every wetland of the country including those nearby cities, which pose the greatest risks.
Turtles are ecosystem indicators. Upholding the species can also secure the fate of more than half-a-dozen other globally threatened turtles, mostly residing in non-protected wetlands.
Wetlands around the world are in peril. These delicate habitats are home to up to 40% of the world's species. Moreover, life of about one billion people depends on wetlands.
These fragile, easy-to-destroy habitats are disappearing three times faster than forests. A practice to embrace the wetland guardians can turn the tide of destruction.


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- Research
- Open access
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Effects of ventilation strategy on distribution of lung inflammatory cell activity
Critical Care volume 17, Article number: R175 (2013)
Leukocyte infiltration is central to the development of acute lung injury, but it is not known how mechanical ventilation strategy alters the distribution or activation of inflammatory cells. We explored how protective (vs. injurious) ventilation alters the magnitude and distribution of lung leukocyte activation following systemic endotoxin administration.
Anesthetized sheep received intravenous endotoxin (10 ng/kg/min) followed by 2 h of either injurious or protective mechanical ventilation (n = 6 per group). We used positron emission tomography to obtain images of regional perfusion and shunting with infused 13N[nitrogen]-saline and images of neutrophilic inflammation with 18F-fluorodeoxyglucose (18F-FDG). The Sokoloff model was used to quantify 18F-FDG uptake (Ki), as well as its components: the phosphorylation rate (k3, a surrogate of hexokinase activity) and the distribution volume of 18F-FDG (Fe) as a fraction of lung volume (Ki = Fe × k3). Regional gas fractions (fgas) were assessed by examining transmission scans.
Before endotoxin administration, protective (vs. injurious) ventilation was associated with a higher ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2) (351 ± 117 vs. 255 ± 74 mmHg; P < 0.01) and higher whole-lung fgas (0.71 ± 0.12 vs. 0.48 ± 0.08; P = 0.004), as well as, in dependent regions, lower shunt fractions. Following 2 h of endotoxemia, PaO2/FiO2 ratios decreased in both groups, but more so with injurious ventilation, which also increased the shunt fraction in dependent lung. Protective ventilation resulted in less nonaerated lung (20-fold; P < 0.01) and more normally aerated lung (14-fold; P < 0.01). Ki was lower during protective (vs. injurious) ventilation, especially in dependent lung regions (0.0075 ± 0.0043/min vs. 0.0157 ± 0.0072/min; P < 0.01). 18F-FDG phosphorylation rate (k3) was twofold higher with injurious ventilation and accounted for most of the between-group difference in Ki. Dependent regions of the protective ventilation group exhibited lower k3 values per neutrophil than those in the injurious ventilation group (P = 0.01). In contrast, Fe was not affected by ventilation strategy (P = 0.52). Lung neutrophil counts were not different between groups, even when regional inflation was accounted for.
During systemic endotoxemia, protective ventilation may reduce the magnitude and heterogeneity of pulmonary inflammatory cell metabolic activity in early lung injury and may improve gas exchange through its effects predominantly in dependent lung regions. Such effects are likely related to a reduction in the metabolic activity, but not in the number, of lung-infiltrating neutrophils.
There is little information on the effects of different mechanical ventilation strategies on in vivo regional lung inflammation. Nonetheless, reduction in regional inflammation is frequently proposed as the rationale for the benefit associated with protective ventilation in patients [1–3].
Pulmonary neutrophilic inflammation, a major process in the early stages of acute lung injury (ALI) [4, 5], is increasingly being assessed by measuring the net 18F-fluorodeoxyglucose (18F-FDG) uptake rate (Ki) using positron emission tomography (PET) [6–11]. The current concept during ALI, derived from experimental studies, is that 18F-FDG uptake is determined predominantly by the combination of the absolute number of lung-infiltrating neutrophils and their metabolic activity [7, 10, 12]. In terms of kinetics modeling, Ki is the product of two parameters: the phosphorylation rate constant (k3, a surrogate of hexokinase activity) and the distribution volume of 18F-FDG as a fraction of lung volume (Fe) [13]. Accordingly, a similar net 18F-FDG uptake rate could result from a large number of inflammatory cells with low metabolic activity (low k3) as well as from a smaller number of cells with high metabolic activity (high k3). Such distinct conditions could represent different pathophysiological mechanisms through which mechanical ventilation strategies alter lung neutrophilic inflammation. Indeed, different biological features in the presence of distinct k3 have been observed in fields where 18F-FDG kinetics has previously been used, such as oncology. For instance, a high value of k3 was associated with poor prognosis in leukocyte malignancies [14, 15], and a low value of k3 was associated with effective anticancer therapy [16, 17].
Previous studies documenting leukocyte infiltration in ventilator-induced lung injury (VILI) have focused on established injury [18]. However, the activity of leukocytes can be independent of the number of infiltrated cells, and the behavior of such leukocytes may depend on the stage of development of the injury and on the approach to ventilation. Although protective ventilation appears to affect the regional distribution of inflammation [19], it is not known whether ventilation strategy influences regional inflammatory cellular metabolic activity (for example, assessed by k3). PET-based methodology can be used to quantify regional lung 18F-FDG kinetics during ALI [20] and other pulmonary inflammatory conditions. We have previously shown in a model of two-hit ALI (VILI + endotoxemia) that both regional aeration and perfusion are associated with regional 18F-FDG uptake [8]. In the current study, we combined 18F-FDG-PET measurements of neutrophilic inflammation with PET assessments of perfusion and aeration in a sheep model to determine the impact of ventilation strategy on regional cellular metabolic activity during endotoxemia and to establish the association of this activity with regional changes in aeration and perfusion. We hypothesized that, during early endotoxemic lung injury, protective mechanical ventilation would reduce regional cellular metabolic activity (k3) and reduce the magnitude and heterogeneity of 18F-FDG uptake.
Materials and methods
Experimental preparation
The experimental protocols were approved by the Committee on Animal Care of the Massachusetts General Hospital (Boston, MA, USA). Twelve sheep (mean weight = 22.3 ± 5.9 kg) were fasted overnight and premedicated with intramuscular ketamine (4 mg/kg) and midazolam (2 mg/kg). After intravenous induction of anesthesia with ketamine (4 mg/kg), an endotracheal tube was inserted, in addition to a percutaneous femoral artery catheter (for arterial blood sampling and blood pressure monitoring) and a pulmonary artery catheter (right internal jugular vein) [10]. General anesthesia was maintained with a continuous infusion of propofol and fentanyl [8], and muscle relaxation was maintained with pancuronium (0.1 mg/kg).
Mechanical ventilation
Baseline ventilation during experimental preparation (approximately 1.5 h) consisted of 8 ml/kg tidal volume (VT), 5 cmH2O positive end-expiratory pressure (PEEP) and 20 breaths/min respiratory rate. Prior to endotoxin administration (see the "Experimental protocol" section below), animals were allocated sequentially to protective ventilation (low VT and high PEEP) or injurious ventilation (high VT and low PEEP), which was continued for 2 h. Protective ventilation comprised 8 ml/kg VT and titration of PEEP such that the plateau pressure (Pplat) was 30 cmH2O [3]. These settings were based on a clinically relevant strategy aimed at maximizing alveolar recruitment while limiting hyperinflation [3]. Injurious ventilation consisted of zero PEEP (0 cmH2O) and titrated VT, such that Pplat was 30 cmH2O. This strategy was aimed at producing both cyclic recruitment-derecruitment and volutrauma while limiting hyperinflation by applying the same Pplat levels used in the protective strategy. Volume-controlled ventilation was used in all cases.
A recruitment maneuver (continuous positive airway pressure of 40 cmH2O during 40 s [21]) was performed at the beginning of the experiment, before adjusting PEEP or VT. Inspired fraction of oxygen (FiO2) was titrated to a target arterial oxygen saturation greater than 88%, a 1:2 inspiratory-to-expiratory time ratio and an 18 breaths/min respiratory rate and adjusted to maintain arterial carbon dioxide tension at 32 to 45 mmHg.
Positron emission tomography imaging protocol and processing
The imaging methods and analysis we used have been described in detail previously [10, 22–24]. PET images consisted of 15 axial slices (slice thickness = 6.5 mm), corresponding to approximately 70% of the lung [24]. Three different modalities of PET scans were performed: (1) transmission scans to correct for attenuation in emission scans and to calculate fgas from regional tissue density, which was used to categorize the pulmonary parenchyma as nonaerated (fgas < 0.1), poorly aerated (0.1 ≤ fgas < 0.5), normally aerated (0.5 ≤ fgas < 0.85) and hyperinflated (fgas ≥ 0.85) [25]; (2) 13N[nitrogen] (13NN) emission scans using a bolus injection of 13NN-saline to measure regional pulmonary perfusion and shunt fraction [23, 26]; and (3) 18F-FDG emission scans to quantify regional metabolic activity using 18F-FDG kinetics. Doses of 5 to 10 mCi of 18F-FDG were infused for 60 s at a constant rate through the central venous catheter. Acquisition time of the dynamic PET scans was 75 min starting simultaneously with the beginning of 18F-FDG infusion.
The lung field was delineated using perfusion and gas fraction images [11, 27, 28]. The whole field was divided for analysis into three horizontal adjacent regions of interest (ROIs) of equal vertical height (nondependent, middle and dependent).
Modeling of 18F-fluorodeoxyglucose kinetics
Inside cells, 18F-FDG is phosphorylated by hexokinase to 18F-FDG-6-phosphate, which accumulates in proportion to cellular metabolic rate. 18F-FDG net uptake rate was calculated by fitting the 18F-FDG kinetics with the Sokoloff three-compartment model for three isogravitational ROIs defined along the vertical axis: dependent, middle and nondependent [13]. This model is composed of one blood compartment and two tissue compartments, with the latter two representing a precursor and a metabolic compartment (Figure 1). The transfer rate constant k3 in this model characterizes 18F-FDG phosphorylation to 18F-FDG-6-phosphate (metabolic compartment), which is proportional to hexokinase activity and has been associated with cellular metabolic activity [16, 29]. The 18F-FDG net uptake rate is computed as Ki = Fe × k3, where Fe is the distribution volume of 18F-FDG as a fraction of lung volume [13, 20, 30].
To account for potential effects of lung inflation and blood volume on regional Ki, we also standardized Ki by lung tissue fraction, thus computing a specific Ki as follows: Kis = Ki/ftissue, where ftissue = (1 − fgas − fblood) and fblood is the fractional volume of the blood compartment obtained from the Sokoloff model. Kis is proportional to 18F-FDG uptake per gram of lung tissue. The Patlak two-compartment model [31] was used to compute 18F-FDG net uptake rate at the voxel level (KiP) to calculate the spatial heterogeneity of 18F-FDG uptake using the standard deviation (SD(KiP)) and to construct parametric images [20].
Experimental protocol
Each sheep was placed supine in the PET scanner with the caudal end of the field of view just superior to the dome of the diaphragm. Physiological data and transmission and 13NN emission scans were acquired both at the start and after 2 h of mechanical ventilation, and the 18F-FDG scan was performed at the end of the study. After the initial set of scans, all sheep received a continuous infusion of endotoxin (Escherichia coli O55:B5, 10 ng/kg/min intravenously; List Biological Laboratories Inc, Campbell, CA, USA).
Histological analysis
Lungs were excised at the end of the experiment and fixed with Trump's fixative (BBC Biochemical, Mt Vernon, WA, USA) at a pressure of 25 cmH2O. Blocks of lung tissue were sampled from ventral and dorsal regions and embedded in paraffin. Sections of 5-μm thickness were cut, mounted and stained with hematoxylin and eosin for light microscopy. Lung neutrophil counts and semiquantitative ALI scores [32] were assessed in 40 randomly selected high-power (×400 magnification) fields per animal (10 per region, 2 regions per lung) by two investigators (NP and MT) who were blinded to the group assignment. This procedure included two steps. First, a JPEG picture was obtained for each field and analyzed using dedicated software (Image-Pro Plus version 6.0; MediaCybernetics, Rockville, MD, USA). Each neutrophil was tallied and marked independently by investigators, and an overlay image was created. Second, for each single field, the values obtained were compared and, in cases of discrepancies in neutrophil counts between investigators, the histologic images were compared and discrepant neutrophil marks were discarded. This approach might have led to a slight underestimation of neutrophil counts but ensured better specificity. A final neutrophil count was obtained and expressed as neutrophils/field/unit of tissue, whereupon normalization for the tissue fraction of each field was performed to account for differences in regional lung inflation. Independent investigators had good agreement as to neutrophil counts in the injurious ventilation group (Lin's concordance correlation coefficient = 0.95) and the assessment of lung injury scores (κ = 0.65).
Statistical analysis
Data are expressed as mean ± SD if normally distributed or, if not, as median [25% to 75% interquartile range]. We compared physiological values (before and after mechanical ventilation and between ventilation groups) and PET-acquired data (between ventilation groups and isogravitational ROIs) using two-way analysis of variance for repeated measures when data or their log transformation displayed a normal distribution. Data that displayed a nonparametric distribution were compared using the Friedman rank-sum test.
Baseline physiological variables
Protective ventilation yielded lower cardiac output (P < 0.05) and higher pulmonary vascular resistance (P < 0.001) after 2 h of mechanical ventilation and endotoxemia, despite similar baseline values (Table 1). Blood neutrophil counts decreased significantly in both groups following endotoxin administration (P < 0.05).
Oxygenation, regional aeration and perfusion before endotoxin administration
Before endotoxin administration, protective ventilation was associated with a higher overall lung gas fraction (fgas = 0.71 ± 0.12 vs. 0.48 ± 0.08; P = 0.004) and a better ratio of partial pressure of oxygen in arterial blood (PaO2) to FiO2 (PaO2/FiO2 = 351 ± 117 mmHg vs. 255 ± 74 mmHg; P < 0.01) compared with injurious ventilation, despite no difference in venous admixture (0.15 [0.07 to 0.36] vs. 0.24 [0.03 to 0.49]; P = 0.89) (Table 1). Protective ventilation resulted in higher degrees of regional fgas in the middle and dependent lung regions (Figure 2A) compared with injurious ventilation. The amount of hyperinflated voxels was lower than 1% in both the protective and injurious ventilation groups.
Regional perfusion fraction with protective (vs. injurious) ventilation was lower in middle regions and higher in dependent regions (Figure 2B). There was a significant vertical dependence of perfusion in both groups at baseline (P < 0.01). Regional shunt also varied with isogravitational region (P < 0.001), but not with ventilation strategy, and was lower in dependent regions with protective vs. injurious ventilation (Figure 2C).
Oxygenation, regional aeration and perfusion after endotoxin administration
Following 2 h of endotoxin administration and mechanical ventilation, oxygenation decreased significantly in both groups (P < 0.05). Global and regional (Figure 2A) lung aeration for both groups remained stable. Perfusion distribution to each isogravitational lung region was also maintained (Figure 2B). However, with injurious ventilation, there was a significant increase in shunt fraction in the dependent lung regions (P < 0.01), which did not occur with protective ventilation (Figure 2C).
Compared to injurious ventilation, protective ventilation after 2 h of endotoxemia was associated with better oxygenation (PaO2/FiO2 = 261 ± 112 torr vs. 162 ± 47 torr; P = 0.05) and a trend toward lower venous admixture (0.37 [0.21 to 0.48] vs. 0.60 [0.37 to 0.75]; P = 0.06) (Table 1). Protective ventilation after endotoxin administration was associated with a lower perfusion fraction in middle regions (0.26 ± 0.08 vs. 0.37 ± 0.06; P < 0.05) but a higher perfusion fraction in dependent regions (0.66 ± 0.10 vs. 0.52 ± 0.08; P < 0.05) (Figure 2B). Regional shunt varied with isogravitational region (P < 0.001) and ventilation strategy (P < 0.01), with significant interaction (P < 0.001), and was reduced in dependent regions in the protective ventilation group (Figure 2C).
18F-fluorodeoxyglucose uptake magnitude and topographical distribution
After endotoxin and 2 h of mechanical ventilation, global Ki, computed using the Sokoloff model, tended to be lower in the protective ventilation group (0.0056 ± 0.0029/min vs. 0.0102 ± 0.0053/min; P = 0.09) (Figure 3). At the regional level, there was a significant effect of isogravitational region (P < 0.001) and a trend toward a significant effect of ventilation strategy on Ki (P = 0.059) with significant interaction (isogravitational region × ventilation strategy; P = 0.005) (Figure 4A). In the dependent regions, Ki was lower with protective ventilation than with injurious ventilation (0.0075 ± 0.0043/min vs. 0.0157 ± 0.0072/min; P < 0.01) (Figure 4A). When differences in lung inflation and tissue volume were accounted for (KiS) (Figure 4B), the significant interaction between ventilation strategy and isogravitational region on KiS was maintained (P = 0.004), as was the independent effect of isogravitational region (P = 0.001).
In order to understand the factors contributing to the changes in regional Ki, we studied its components: the cellular metabolic activity (k3) and the distribution volume of 18F-FDG as a fraction of lung volume (Fe, where Ki = k3 × Fe). k3 was significantly lower with protective ventilation than with injurious ventilation (P = 0.002) and was highest in dependent regions of injurious ventilation (Figure 4C). In contrast, Fe varied significantly by isogravitational region (P = 0.022) (Figure 4D).
Protective (vs. injurious) ventilation was associated with a threefold reduction in the spatial heterogeneity of pulmonary 18F-FDG uptake (indicated by SD(KiP); 0.0045 ± 0.0023/min vs. 0.0126 ± 0.0069/min; P < 0.01), reflecting a more homogeneous distribution of metabolic activation throughout the lung. The heterogeneity of 18F-FDG uptake distribution SD(KiP) correlated with KiP in both groups, with similar slopes (Figure 5); however, the protective ventilation group exhibited a lower y-intercept (0.0009 ± 0.0013/min vs. 0.0033 ± 0.0012/min; P < 0.01), such that for equivalent mean Ki values, the heterogeneity of Ki was lower with protective ventilation than with injurious ventilation.
Regional lung histology and 18F-fluorodeoxyglucose uptake values
Endotoxin infusion was associated with marked systemic neutropenia in both ventilation groups (Table 1). Median ALI scores were less than 2 on a scale of 12 in the dorsal and ventral regions of both groups, without a statistically significant difference (Table 2). No significant difference was observed in global lung neutrophil counts between the protective and injurious ventilation groups (53.2 ± 23.5/field/unit of tissue vs. 43.2 ± 11.6/field/unit of tissue; P = 0.24). At the regional level, there was no difference between groups (P = 0.33), but there was a significant effect of lung region on neutrophil count (P < 0.01) with no interaction (P = 0.87). In dependent regions, lung neutrophils of the injurious ventilation group exhibited higher k3 values than those of the protective ventilation group (Figure 6). There was a significant correlation between Fe and regional neutrophil counts found in histological analysis (r = 0.43; P = 0.046).
Our main findings are that after only 2 h of the combined effects of endotoxemia and mechanical ventilation, a protective ventilation strategy that maximized alveolar recruitment and limited lung distension led to the following results: (1) decreased rate of phosphorylation of 18F-FDG (k3), which reflects metabolic cellular activity; (2) reduced heterogeneity of 18F-FDG uptake rate throughout the lung; (3) decreased magnitude of 18F-FDG uptake in the whole lung, predominantly by reducing 18F-FDG uptake in the poorly aerated, dependent lung regions, despite greater perfusion, and thus more endotoxin exposure in these areas in the protective than in the injurious ventilation strategy; and (4) no reduction in the number of lung-infiltrating neutrophils. These findings suggest an effect of the protective ventilation strategy with low VT in modulating the intensity and topographical distribution of regional pulmonary neutrophilic inflammation during mechanical ventilation following endotoxemia. The intensity of inflammation was best reflected in reduction of inflammatory cell metabolic activity (that is, k3), even when regional neutrophil numbers were similar.
Animal model
We used a well-established model of endotoxemia because of its reproducibility, its ability to induce pulmonary vascular neutrophil sequestration within the first hour [33] and thus its relevance to study neutrophil activation [34]. In previous studies, the current endotoxin dose allowed for survival of awake animals for 24 h [35, 36]. Thus, in terms of lung injury, the initial 2 h of endotoxin exposure represent early events, as attested by very low lung injury scores obtained by histological analysis. The scatter of PaO2/FiO2 ratio values obtained after 2 h of mechanical ventilation and endotoxin illustrates the intersubject variability of lung function impairment, even after standardized lung injury. Nevertheless, the protective ventilation strategy produced significantly higher PaO2/FiO2 levels than the injurious ventilation strategy. Our regional PET measurements confirmed that the model also yields a broad range of regional lung expansion with minimal hyperinflation (no regional fgas value above 0.9) and appropriately reflects the lung recruitment and reduction in shunting in dependent lung regions produced by protective ventilation. In addition, the approach to protective ventilation chosen in the current experiments closely reflects the management strategy used in one of the key randomized controlled clinical trials of acute respiratory distress syndrome (ARDS) [3], in which VT was fixed and the level of PEEP adjusted to a predetermined Pplat, although important differences include the volume preset ventilation used in the current study as well as the normal initial lung compliance. In fact, we chose to set the VT at 8 ml/kg to limit alveolar hypoventilation related to the larger anatomic dead space in sheep than in humans (normal VT in spontaneously breathing sheep is approximately10 ml/kg) [37]. That VT setting provided a clear distinction from the injurious model, although it exceeded the current clinical recommendation for VT of 6 ml/kg of predicted body weight in ARDS patients [38, 39] and even lower settings (4.2 ml/kg) for ARDS patients with high Pplat [40]. Hemodynamics remained stable over time, which is consistent with the administration of mild doses of endotoxin. The lower cardiac output in the protective group was likely due to higher intrathoracic pressure associated with higher PEEP levels.
Early changes in regional 18F-fluorodeoxyglucose uptake during acute lung injury
In the acutely injured lung, PET imaging of the glucose analogue 18F-FDG functions as a noninvasive in vivo measure of neutrophilic inflammation [7, 10, 12, 41]. Recent human and animal studies of ALI and ARDS indicate that total 18F-FDG uptake may provide insight into disease mechanisms [8, 10, 11, 42, 43] and predict respiratory failure [44], as well as being useful in evaluation of therapy [45]; however, the impact of ventilation strategy (that is, protective vs. injurious) on intensity or topographic activity has not previously been reported. The current findings indicate, at least in the current model, that mechanical ventilation has an important effect in determining the regional distribution and degree of early neutrophilic inflammation. Protective ventilation resulted in more homogeneously distributed Ki and lower Ki values in dependent lung regions. Furthermore, we observed a trend toward reduction in pulmonary 18F-FDG uptake with protective ventilation, despite similar histological lung injury scores and equal end-inspiratory pressures. These results are compatible with the concept that ventilation strategy plays an early pathogenic role in determining the profile of inflammatory cell distribution before lung injury is established [46] and emphasize that the prevention of VILI should be a key aspect of patient management, even when mechanical ventilation period and the underlying level of injury are limited [47].
Our in vivo measurements substantiate prior speculation that heterogeneous inflammation may be an important element of the pathogenesis of ALI and ARDS [19, 48]. However, there are conflicting data on the topography of early lung inflammation during ALI and ARDS. A previous study in a surfactant-depleted small animal model (saline lavage rat model) indicated that aerated, nondependent regions were those predominantly affected by mechanical ventilation without limitation of end-inspiratory pressure [49]. In that study, surfactant depletion promoted the derecruitment of dependent regions and thus likely led to overexpansion of nondependent regions substantially more than in the injurious ventilation group in the current study. This phenomenon was amplified by the application of larger VT in the rat model (25 ml/kg), resulting in a much larger nondependent strain [49]. Recently, researchers in a study in which a sheep model of endotoxemic ARDS and mechanical ventilation was used reported that inflammatory changes occurred predominantly in apical lung regions, but not in basal regions [50]. Such topographic differences with our injurious ventilation group might be related to the application of PEEP, which prevented the development of inflammation in dorsal regions, likely through the reduction of low lung volume mechanisms. Our results in an animal model of size comparable to the human and using clinically relevant Pplat limits indicate that, in early endotoxemia during mechanical ventilation without PEEP, inflammation occurs in the dependent regions. This suggests that those regions may be targeted as key foci indicating inflammatory activity with the potential for PET imaging to quantify treatment response.
There is controversy regarding the relationship between regional 18F-FDG uptake and regional aeration and perfusion in heterogeneous lungs [51]. In a model of endotoxemic ALI and mechanical ventilation [8], we previously suggested that higher regional 18F-FDG uptake was associated with regional extremes in aeration (low and high) and high perfusion. This suggested an effect of both low-volume lung injury and hyperinflation on 18F-FDG uptake and presumably indicated a link between regional neutrophilic inflammation and regional exposure to endotoxins, inflammatory mediators and cells. In this context, the reduced 18F-FDG uptake in dependent regions of the protective ventilation group, despite an increase in perfusion of these regions, suggests that the effect of the protective ventilation strategy on reducing 18F-FDG uptake was predominantly related to increased regional aeration. This effect could have been partially due to the reduction in the shunt fraction of dependent regions, as hypoxemia promotes neutrophil influx into shunting regions through increased neutrophil-endothelium interaction [52].
Cellular factors contributing to 18F-fluorodeoxyglucose uptake
Pulmonary 18F-FDG uptake is determined by both cell numbers and cellular metabolic activity [20, 30, 41]. Individual cell activation is associated with increased energy requirements, and enhanced glucose uptake (that is, cellular metabolic activity) reflects the energy involved in key functions (for example, migration, phagocytosis, degranulation, generation of toxic reactive oxygen intermediates and cytokine production) [53, 54]. Quantification of cell activation independent of the inflammatory cell number may be particularly relevant during ALI, given the major role of neutrophil activation in the early stages of ALI [55]. Indeed, previous studies have suggested that lung injury is affected mainly by neutrophil activation rather than by their number [41, 55, 56] that the transfer rate (k3 in this analysis) obtained from the analysis of 18F-FDG kinetics associated with hexokinase activity [13, 20] allows for such assessment [16].
Our results suggest that the effect of ventilation strategy in reducing 18F-FDG uptake during early endotoxemia was predominantly through its effect on cellular metabolic activity (k3), not on cell number (Fe). Metabolic activity, k3, was the predominant contributing factor to the reduction in 18F-FDG uptake by protective (vs. injurious) ventilation and was significantly reduced in dependent lung regions in the protective ventilation group. Given that the cells taking up 18F-FDG are predominantly neutrophils in this model [7, 8, 12, 30, 41], the lower k3 value mainly reflects lower metabolic activity of lung-infiltrating neutrophils during protective ventilation with higher PEEP and lower VT.
This predominant role of k3 was confirmed by the finding of lower Ki with protective vs. injurious ventilation for a similar range of regional neutrophil quantities in both groups, measured independently and using direct histological methods. Moreover, we found lower k3 values per neutrophil in dependent regions of the protective (vs. injurious) ventilation group (Figure 6). This novel finding leads us to speculate that a reduction in lung neutrophil activity could be a mechanism by which protective ventilation improves outcomes of ALI and ARDS patients [3, 38]. This result also suggests that quantification of cell activation (k3) allows for characterization of differences in the type and severity of ALI, even when inflammatory cell numbers are similar. This observation is compatible with the reported relationship between k3 and severity of disease in cancer research, where cell activity was indicated as a marker of severity [14, 16, 17], and suggests that k3 could be a sensitive tool with which to monitor noninvasively early changes in lung inflammation in ALI and ARDS. The observed dissociation between cell numbers and metabolic activity suggested by the current study in an experimental model of ALI paves the way for the development of new methods for quantifying the effects of mechanical or pharmacological interventions in ALI and ARDS.
Factors associated with modulation of lung inflammation by a protective ventilation strategy
Different factors could explain the reduction in neutrophil activation associated with protective ventilation. First, there are those related to regional lung mechanics. Given that the same Pplat was used in all animals, group differences in 18F-FDG uptake should be due to different PEEP volume and VT. Because significant differences in 18F-FDG uptake were evident in the dependent poorly aerated lung regions, low-volume lung injury is a likely factor. Such injury is related to processes such as repetitive opening and closing of distal airways and alveoli [57, 58], concentration of regional mechanical forces [59] and propagation of air in fluid-filled airways [60]. In fact, this low-volume effect associated with smaller PEEP levels would be magnified by the concomitant increase in VT [61]. Because dependent lung units with mechanical instability express higher cytokine levels than nondependent units [19], reduction in the number of those units by protective ventilation could decrease the activation of inflammatory cells and result in lower Ki independently of the number of neutrophils.
The linear relationship between SD(Kip) and Kip for both groups is suggestive of a positive feedback mechanism in the generation of the spatial distribution of Kip. Points were tightly distributed around the regression line and showed an increase in Kip heterogeneity as the average inflammation level increased, with an approximately constant coefficient of variation. The coefficient of variation is related by a monotonic, increasing transformation to the standard deviation of a log-normal distribution [62]. This distribution describes multiplicative phenomena and is frequently encountered in lung physiology [63, 64]. We speculate that a multiplicative factor in our study could have been produced by triggering of regional lung inflammation with parenchymal cell activation and release of inflammatory mediators. This would result in chemotaxis and additional regional cellular activation, which would amplify the inflammatory process [5, 64]. In contrast, less inflamed lung regions would not demonstrate such amplification. These changes would result in an increase in the mean and SD Kip values. Our results suggest that such an increase occurs according to a well-defined quantitative relationship.
Methodological considerations and limitations
First, we used two strategies of ventilation (low VT/high PEEP vs. high VT/low PEEP) designed to produce clearly different degrees of lung inflation magnitude and heterogeneity in order to test the effect of mechanical ventilation on regional cellular metabolic activity. Thus, our results cannot be directly extrapolated to the clinical context. In fact, whereas the maximal recruitment strategy produced a trend towards lower mortality in patients with severe ARDS, it led to the opposite trend in patients with predominantly mild ARDS (PaO2/FiO2 >181 mmHg) [3]. Accordingly, further studies will be needed to exactly determine settings consistent with "protective ventilation" for the individual patient. Second, the observed relation between histological neutrophil counts and the distribution volume of 18F-FDG (Fe) was weak, suggesting that other cell types contributed to 18F-FDG uptake, as previously shown [65]. The cellular mechanisms associated with increased 18F-FDG uptake, specifically changes in k3, were not investigated in this study and could involve metabolic changes associated with the polarization and migrational status of lung neutrophils [54], Toll-like receptor 4-dependent mechanisms [66, 67] and the regional production of neutrophil chemoattractant cytokines [68].
Our present study shows that, at early stages of endotoxemic ALI, mechanical ventilation strategy strongly influences the intensity and distribution of neutrophil inflammation in the lungs. Protective ventilation (increased alveolar recruitment, low VT) improved gas exchange and reduced inflammatory cell activity, especially in dependent lung regions. The main cause of reduced inflammatory cell activity was lowered neutrophilic metabolic activity (phosphorylation rate), not changes in regional cell counts. This suggests that mechanical ventilation may modulate regional neutrophilic inflammation in early stages of endotoxemic ALI.
Key messages
At early stages of endotoxemic ALI, mechanical ventilation strategy influences the intensity and distribution of neutrophil inflammation in the lungs.
Protective ventilation improved gas exchange and reduced inflammatory cell activity in dependent lung regions.
The main cause of reduced inflammatory cell activity was lowered neutrophilic metabolic activity.
Acute lung injury
- f gas :
Gas fraction
Positron emission tomography
Region of interest
Ventilator-induced lung injury.
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The authors thank Dr Sandrine Katsahian for statistical assistance. This work was supported by National Heart, Lung, and Blood Institute (NHLBI) grant 5R01-HL086827. GM received salary support from NHLBI grant 5K08HL076464. NP received a scholarship from the Société de Pneumologie de Langue Française (SPLF).
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NP, EC, TWe, TWi, BK and MVM designed the study. NP, EC, TWe, MT, TWi, GM, RH, JV and MVM performed the experiments and analyzed the results. NP, EC, TWe, GM, MT, TWi, RH, JV, BK and MVM wrote and corrected the manuscript. All authors read and approved the final manuscript.
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de Prost, N., Costa, E.L., Wellman, T. et al. Effects of ventilation strategy on distribution of lung inflammatory cell activity. Crit Care 17, R175 (2013). https://doi.org/10.1186/cc12854
DOI: https://doi.org/10.1186/cc12854


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