Chapter 3: Cytokine Scream
The macrophage screamed.
U-1196 had heard such screams before, but still, it unnerved her every single time. During her stay in the Bone Marrow Academy, she learned not only were macrophages the elegant caretakers and ruthless defenders of the world, but they were also known as the heralds of battle. As Antigen-Presenting Cells, they signal other white blood cells to ongoing threats. It was not unusual to see a macrophage to be the first one in battle.
U-1196 remembered her instructors teaching her class that once macrophages encounter a massive antigen threat, they would bellow out Cytokine screams to rally allies to their position. This statement got a lot of curious glances from her fellow classmates. Up to this point in their training, they had only seen their macrophage instructors as their nurses and teachers. They always watched them strolling with a smile or sitting in a cafe sipping tea. Of course, they know their teachers were also white blood cells, but they have never seen them in an actual fight.
Until they did.
U-1196 could still remember her first battle with a macrophage at her side vividly. It was in a battle fought in the left knee. The world came into a crashing fall, and the knees got scraped on impact. Emergency alarms blared across the blood vessels, ordering all available neutrophils to the breach. Inflammation procedures had already begun, and it just so happened she was part of the first wave of reinforcements.
The scraped knee was a scene of utter carnage. An enormous bacterial warhost had just invaded the world. Mangled corpses of foe and allies alike littered the battlefield, with the initial defenders wholly wiped out. Those that survived could only wish they didn't, as the bacteria warhost impaled them on top of crosses for other white blood cells to see and tremble. U-1196 charged directly into the fray of battle, with her mouth wide open into a roar of defiance. She hacked and skewered and slashed and lunged at the enemy. She annihilated the invading bacteria with no mercy given and no quarters sought.
But still, they kept coming. She could feel a searing rage within her, fueling her in administering destruction on the bacterial warhost, but it was not enough.
Never. Enough.
Then, she heard the nucleus-splitting screams.
In complete synchronicity, the macrophages, her former instructors and caretakers, all let out a scream that shook her to her very core.
The screams were too loud and too extreme for her young cellular form that, for a moment, she even thought the elegant phagocytes were attacking her. But then, she felt the change within her starting to take shape. The ambers of her rage rekindled with one of eternal fire. She suddenly felt renewed with purpose and righteous fury. She charged again into the center of battle without fear or hesitation.
The last thing she remembered of the battle was her vision blurring in crimson as she lost herself to the Cytokine scream.
U-1196 gritted her teeth as she received a heavy stream of Tumor-Necrosis-Factor codes, also known as TNF, and a dozen Interleukin codes embedded in the cytokine scream into her very being. These codes began deactivating her internal limiters, which significantly heightened her state of aggression. She could even feel her cytoplasm boiling for carnage, and she could hear her mitochondrion beating furiously in her chest. Even with only one macrophage doing the screaming, the cytokine activation process still took all her self-control to not lose within the rage.
J-1178, on the other hand, didn't even know what to do.
The veteran could see her kouhai fall to her knees with her hands covering her ears. She had her eyes closed shut while her mouth gaped into a wide soundless agony. J-1178 was still a young neutrophil, and this was the first time she'd experience a cytokine activation.
A cytokine scream from a macrophage could sometimes be too overwhelming for new recruits.
U-1196 remembered the aftermath of the battle of the scraped knee. She was on her knees vomiting out cellular fluid. Her nucleus felt like it wanted to split into two. She looked at both of her hands and saw them shaking. It would take her a couple of circadian cycles before her hands finally stopped trembling.
Her instructors assured her that everyone would eventually get used to it. However, even to this day, she still feels unnerved by a macrophage's terrifying scream.
"Get up!" U-1196 shouted at her kouhai. "Nanahachi, get up!"
"Onee-sam… I..." J-1178 gritted her teeth. With her hands still in her ears, she forced herself back to her feet. "I feel…"
But she fell back to her knees not because she felt weak but because she didn't know how to process the incoming streams of data into herself. Her bone marrow training was rushed, and she never got the ample time even to be forewarned on what a cytokine scream could do to her.
Like the veteran, the young neutrophil sensed her limiters getting deactivated, and a primal urge for violence boiled up from her organelles.
Her vision became tainted with a crimson hue. She let out her own nucleus-splitting shriek, which echoed throughout the corridor.
J-1178 slammed a fist into the glass pane, cracking it into an intricate cobweb pattern of broken glass.
"Nanahachi!" U-1196 shouted again before wincing from the internal flames burning within her. She grunted and then once again barked a command to her kouhai. "J-1178, stand attention!"
The young neutrophil snarled at her senior with no sign of backing down. She even seemed poised to pounce at U-1196 if she could not find a suitable prey within the next minutes.
But then, clarity came to her senses. The red haze in her vision disappeared, and she already felt a semblance of sanity coming back to her.
The nucleus-splitting scream had died down, blessing the two with only the frantic wails of fleeing pneumocytes.
J-1178 blinked a couple of times before her vision finally focused on her senior.
"Onee-sama?" She asked, unsure of what just happened to her. "What just…"
"A cytokine scream," U-1196 answered her before she could ask the question. She tried to maintain a grim but neutral face bereft of any judgment at the young neutrophil's sudden loss of control. "There will be more of that in the future, Nanahachi. Prepare yourself."
"I…" J-1178 stared at the cracked glass pane in front of her and then on her trembling hands. "That was…"
Before she could say anymore, emergency Klaxons blared a second time. Caution signs located all across the capillary started blinking in bold crimson letters.
Then the selectin switch U-1196 had her hand firmly on its sensors began to heat up. The veteran neutrophil gritted her teeth as she ignored the searing pain on her palm.
"Onee-sama, your hand!" J-1178 started to approach her, but the veteran neutrophil waved her off with her other hand.
"It's nothing," U-1196 assured her kouhai with a pained expression. "The cytokine scream has also activated the endothelial cell walls of this capillary."
As if on cue, the box casing beside the E-Selectin switch began to open, revealing another scanner switch for another hand. The label on top of the switch read, Intercellular Adhesion Molecule, or ICAM.
Selectins are a family of Cell Adhesion Molecules, or CAMs, found in the surface of endothelial cells and leukocytes. When a macrophage battles out an infection, they release a bunch of cytokine signals that activate the E-Selectins of endothelial cells. Once activated, they help with the adhesion of white blood cells with the endothelial cell wall, anchoring them in place for extravasation.
"Nanahachi, brace yourself," U-1196 warned her kouhai. "Once I bind my hands to this ICAM switch, I need you to ready yourself for diapedesis, you understand?"
The young neutrophil nodded before grimacing from pain.
U-1196 nodded back before removing her right glove. She then placed her bare right hand on the ICAM switch. The switch's scanner obtained a detailed readout of her embedded Integrin code. A few seconds passed, and the ICAM switch turned green, accepting her Integrin code as valid.
Then, the Klaxons blared out another warning tune. This time, the pitch was low and long-drawn, which gave it an ominous impression.
With the Selectin and ICAM switch now activated, U-1196 removed her hands away from their palm scanners as she unsheathed her blade again.
The capillary began to shake. The lights on the ceiling dimmed as emergency lights started to lit up. A bunch of fleeing pneumocytes cried out at the sudden trembling. They knew what was about to happen next, and some tried to grab onto guard rails to secure themselves.
U-1196 didn't have time to warn the cowardly pneumocytes. They already know the drill. Once the capillary starts to contract, then everything inside not bolted to the floor was free game.
She let out a heavy breath. She faced the glass wall and waited for the panes to contract.
=0=0=0=
The rookie saw the veteran neutrophil up ahead and realized they were already too late.
"Grab the railings!" AA-2153 shouted. "Now!"
The five erythrocytes immediately went to the sides to cling onto the capillary's guard rails as frantic alveolar cells passed them by. They even fastened their carabiner hooks to the railings for extra measure. As if acting on impulse, the five began to huddle together to avoid getting separated.
AA-2153 took the lead of the group while Burns took the rear. Between them huddled Sharp and Blush, respectively, with Freckles directly in the middle.
"Never let go!" The glasses-wearing erythrocyte yelled out as he tightened his grip on the railings. "This will be one heck of a-"
A panic-stricken pneumocyte tried to yank him away from the railings.
"Move away!" screeched the alveolar cell, desperately trying to remove AA-2153 from his position. "You're clotting! That's illegal!"
"Sir! Just… Just grab my ha-" the rookie erythrocyte extended a free hand for the pneumocyte to cling on, but he continued to assault him.
"Let go!" the deranged alveolar cell screamed despite AA-2153 offering his hand for him to grab on. "You're just an erythrocyte! You're replaceable!"
"Stop! Sir, please… Just..."
Sharp, who was at his side, suddenly unleashed an upper kick aimed directly at the pneumocyte's face, which hurled him back a couple of steps.
"Sharp!" AA-2153 cried in horror.
But before the panic-stricken pneumocyte could stager back up, the glass panes of the capillary opened, and everything not bolted to the ground flung out into the cavernous maw of the alveolus.
A/N:
I'm back! It's been a while since I updated this fic. The reason for the delay, aside from real-life issues, is that most of the research I made back in May is no longer updated. For example, I was hoping for Convalescent Plasma Therapy to be considered as a restorative treatment for Covid19, but the studies turn out to be not so promising. As such, I needed to make some adjustments.
Anyways, it's good to be back writing this fic again, especially since Code Black now has an anime! Damn, the first episodes were dark, and I'd like to continue that theme in this story.
Interesting Tidbits:
Extravasation and Diapedesis:
Oh boy, this one is a heavy topic.
Alright, I'll try to explain what I've learned in layman's terms since my head is still spinning on this. Again, I'm no medical expert, and so I might get things wrong here.
When your skin, or in our case, your alveolus, is invaded by antigens, your innate immune system starts to fight them off, which causes inflammation.
So, suppose you get your knee scraped from a bad fall, bacteria from the outside invades the abraded skin deep into your epidermis. Macrophages can sense these bacteria and then starts to investigate. They attack them using phagocytosis, and then they release a signal called 'cytokine', which calls for reinforcements.
In the manga, Dendritic cell is the one that unleashes cytokines. This is true. Dendritic cells also release cytokine when encountering antigens. This is depicted in the manga as Dendritic cell spreading embarrassing pictures of the current Neutrophils, KT, and NK cells back when they are still in school.
In this fanfic, I made it as close as real-life with Macrophages releasing cytokine through a 'cytokine scream'. Of course, macrophages don't scream, but the way they emit cytokine molecules is almost like they're screaming, and this affects a whole bunch of cells in the macrophage's vicinity.
From what I've gathered, there are many kinds of cytokines such as Tumor Necrosis Factor (TNF), Chemokines, and a bunch of Interleukins (IL-1, IL-2, etc.). My head still spins whenever I read articles about these cytokines. Still, they do help in the fight against antigens.
Anyways, when cytokines reach the endothelial cells of the blood vessel or capillary, it activates them to extend microscopic hooks called Selectins and Intercellular Adhesion Molecules. These tiny hooks will help in snagging passing neutrophils in the bloodstream. Basically, they act like velcro.
Neutrophils, on the other hand, when they sense cytokines, they also extend their own tiny hooks such as Integrins to bind with the endothelial cells' Selectins and ICAMs.
In this fanfic, this is depicted by U-1196 scanning her hands with Selectin and ICAM switches. There's actually a mistake in this fanfic in which U-1196 is able to activate the Selectin switch before the macrophage in the Alveolus bellows out a cytokine scream. U-1196 should have waited for the cytokine scream before placing her hand on the Selectin switch if we'll go with an accurate depiction.
Still, it's been more than half a year since I wrote chapter 2, so I'd just let the inaccuracy slide.
Ok, so now a neutrophil has snagged itself on the blood vessel wall, they don't just immediately stop. Instead, the Selectin and ICAM hooks will only slow down the snagged neutrophil's movement, making it roll. So the neutrophil rolls for a couple of micrometers until finally, it stops. Once halted, the neutrophil will then squeeze itself between the blood vessel's walls in a process called 'diapedesis'.
By the way, the cytokines unleashed by the macrophage will also trigger the endothelial cells to contract, which helps the neutrophils to squeeze through. This contraction, or 'extravasation', also lets out blood and fluids outside of the blood vessels.
I believe this is why infected areas start to get inflamed. Fluids escaping from the blood vessels are quite dangerous if they're in the Alveoli. These fluids will fill up the Alveoli, and oxygen can no longer be absorbed into the capillaries.
This is why pneumonia can be quite deadly. Fluids build up inside your lungs, and you'll just drown on your own.
I suggest accessing the Youtube video links below for more information on cytokines, diapedesis, and inflammation.
Anyways, that's all for my layman's explanation on this subject. I hope you all enjoy this update. ^^
Stay safe, everyone!
References:
CYTOKINES : ILs, INFs, TNFs, CSFs and Chemokines (FL-Immuno/04)
Youtube - 9wdZLvNKyQY&list
Acute Inflammation- Educational 3D Animation
Youtube - 1SvEdg94qUA&list
Diapedesis : Extravasation of Neutrophils ( Innate immunity)
Youtube - 2owNMyOO5_Q
Revision History:
- Originally published on January 30, 2021.
