A new wave of research links inflammation to almost all chronic disease.
Sixty years ago, Patricia Mabe took her first-ever breath, inflating new pink lungs with the air of Carbondale, Pennsylvania, home of the nation’s first underground mine; a town that today, despite a long-ago demise of the anthracite industry, still smolders from burning veins of coal.
Mabe’s subsequent inhalations—even before she acquired, at age 15, a smoking habit that would be lifelong—no doubt contained vestiges of a variety of toxins, no matter whether she was outside or in. Her dad, who worked in a mine, was a smoker. Her mother smoked, too.
Whenever Mabe inhaled anything noxious, her body’s defense system recognized foreign molecules in her lungs as the interlopers they were and mounted a functional inflammatory response. Brawny cells called macrophages, among others, stormed her lungs to do away with pathogens and debris while unleashing a barrage of molecular messengers that orchestrated strategic battles and mended damaged cells. Then—and this is every bit as important as their SWAT-team-like arrival—the macrophages would leave with all their assorted artillery in tow once the mission was over. In a healthy system, inflammatory cells are both highly regulated and self-disciplined; they go where ordered, expertly distinguish friend from foe, exert only necessary firepower, tidy up after themselves and then retreat, ultimately restoring calm—also known as homeostasis.
Precise though the immune system may be, some level of self-attack occurs even when all parts are working well. The key is keeping the collateral damage in check.
In fact, how effectively and efficiently any one person controls inflammation is a key determinant of health and disease. Some individuals regulate inflammation better than others. It’s likely that many of us are able to control inflammation at certain times of our lives better than at other times. Why—and how—is the focus of intriguing research that’s implicating how nutrition and inflammation interact in just about every major chronic disease.
"The inflammatory system is like the ocean. It’s beautiful, but also deadly." —Josef Coresh
“There appear to be windows of opportunity when we are good at adapting to what is in our environment, which is intimately related to how we meet and greet and defend ourselves from potential invaders,” says Keith West, DrPH ’86, MPH ’79, the George G. Graham Professor of Infant and Child Nutrition. “We get less good at that as life goes on.”
Over time—likely in response to the toxicity and persistence of cigarette smoke in her lungs—Mabe’s inflammatory response turned pathological. The composition of immune molecules and cells became qualitatively and quantitatively different. Inflammation became too too: There was too much of it; it was too strong for too long. Complicating that scenario, macrophages also became unfit and lingered incompetently in her lungs, clogging her airways.
What once defended her from disease now was causing it.
There's a new buzz among scientists about inflammation, even though it’s been known for ages to be one of the first responses by the immune system to infection and irritation. Inflammation is hot. And not in just a classical “calor” kind of way. Calor—as in heat or fever—is one of four characteristics of inflammation recorded in De medicina, an ancient Roman medical text. The remaining three—dolor, rubor and tumor—translate to pain, redness and swelling, respectively.
“Inflammation is something we have rediscovered in the 21st century,” explains Shyam Biswal, PhD, MS, a professor in Environmental Health Sciences (EHS), “specifically, inflammation as a focal point of chronic disease. People used to think of it as a bystander of disease. But it’s actually a driver.”
If attention to inflammation is spreading like wildfire throughout the research world, an early spark was ignited by Noel Rose, MD, PhD, director of the Center for Autoimmune Disease Research. Having introduced the concept of autoimmunity as a cause of chronic thyroiditis in 1956, Rose now is investigating the causes of magnified inflammatory responses in the hearts of young men for whom transplant is the only cure. A muscle that needs to pump, Rose concedes, is a bad location for excessive scarring to occur as a result of inflammation.
“We’re now looking at the details of inflammation,” he says, “and realizing the benefits from targeting specific parts of the inflammatory response. You have to know which part is doing good and which is doing bad and tailor drugs accordingly.”
It’s not simply the presence or amount of inflammation that’s important, Rose says: “It’s the texture of it; the makeup of the cells that are attracted, the ways in which they are stimulated and the products they release. If you’re getting down to that level, that’s where you find the causes of diseases.”
Among chronic, noninfectious disorders now commonly regarded as “inflammatory” is atherosclerosis, often called hardening of the arteries, says Josef Coresh, MD, PhD ’92, MHS ’92, director of the George W. Comstock Center for Public Health Research and Prevention.
“We’ve known for a long time that inflammation is central to atherosclerosis,” says Coresh, principal investigator of the Johns Hopkins Field Center of the Atherosclerosis Risk in Communities (ARIC) study. “You can see inflammatory cells in the lesions.” (Known as plaques, lesions form in the arteries, hardening them.)
The prospective ARIC study, which first examined 15,792 Americans in 1987 and has followed them ever since, is a key resource for the investigation of many inflammation-related chronic diseases—few of which show their hands so obviously as atherosclerosis.
Researchers who are sleuthing the origins of cancers and diabetes, for instance, have found themselves stumbling time and again on inflammatory roots. Apparently, long ago resolved and seemingly unrelated infections buried deep in people’s pasts might tip the precarious immune system balance, imperceptibly if irrevocably reprogramming it. So too might the persistently simmering, subclinical kind of inflammation caused by excess body fat, for example. One investigative focus is finding the mechanisms that link long ago infections to inflammation and later, chronic diseases. Another is dissecting and tinkering with processes that can block, enhance or otherwise regulate inflammation once the SWAT team has mutinied.
“It’s not simply the presence or amount of inflammation that’s important. It’s the texture of it. That’s where you find the causes of diseases.” —Noel Rose
For instance, Andy Pekosz, PhD, with collaborators from Johns Hopkins Medicine, has demonstrated that epithelial cells harvested from the noses of patients suffering from chronic sinusitis “remember” many generations later that they are different. These cells have comparatively heightened inflammatory responses to various stimuli a month after leaving a diseased nasal environment—despite having been grown and propagated under the same conditions as healthy cells in lab culture dishes.
“This tells us there’s something about these cells that has changed,” explains Pekosz, an associate professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology (MMI). “The detection machinery or the circuitry in the cells from sinusitis patients is reprogrammed to respond differently to factors that stimulate inflammation.”
Understanding this reprogramming of the inflammatory response itself is the holy grail for Pekosz.
“If we could understand how to tune down that heightened response by the epithelial cells, we could relieve the chronic sinusitis,” he says. “The flip side is, if we could, at an opportune and early time point, find a way to increase the inflammatory responses, we might have a very powerful broad tool to use against a number of different viruses, for instance.”
Fiddling even a bit with any discrete part of a delicate and complex system is not without unforeseen consequences, many of which could be perilous, if not immediately, then sometime in the future. (Case in point: Although it provided sweet relief for many with osteoarthritis pain, the anti-inflammatory drug Vioxx, which works by inhibiting an enzyme in the inflammatory pathway called COX-2, was withdrawn from the market in 2004 after a study showed it doubled patients’ risk of heart attacks and strokes after 18 months of use.)
The inflammatory system is like the ocean, according to Coresh: “It’s beautiful, but also deadly,” he says. “As long as it’s calm, you can conduct commerce and fish on it, and without it, you’re dead. But, if it storms, it’s incredibly powerful and can kill you.
“When there’s imbalance in one thing, it’s like a wave that pushes on other things and you get a whole cluster of effects.”
Among the things that both cause and react to system imbalances are messenger proteins called cytokines. The immune system communicates through these versatile factors that float around in the bloodstream. Unlike neurons in the hard-wired nervous system, cells in the immune system are not physically connected to one another.
"If you think of the nervous system as a landline, then the immune system is a cell phone," says Jay Bream, PhD, an MMI associate professor. "Different cocktails of cytokines, in various abundances, play a central role in determining immune responses."
A phenomenon known as a "cytokine storm" can occur if the reaction of the immune system to a pathogen is wildly exaggerated and stimulates too many of the messenger molecules, which in turn activate the same cells that stimulated them, resulting in a dangerous feedback loop. For example, cytokine storms are associated with severe bacterial infections and the onset of septic shock as well as avian influenza (H5N1) infection. Likewise, infection with the deadly Ebola virus is associated with a cytokine storm leading to uncontrolled inflammation.
Cytokine storms can happen in tissues throughout the body. That's because the component parts of the immune system spread far and wide, from the top layer of skin to the deepest recesses of the bowels.
Bream, whose mission is linking cytokines with disease outcomes, studies Interleukin-10 (IL-10): "a lynchpin" he says, "at the nexus of inflammation."
When the volume of IL-10 is turned down low, inflammation happens. When it's blasting, inflammation is tamped down. Bream, co-director of the Becton Dickinson Immune Function Laboratory at the Bloomberg School, has shown that mice prone to express higher levels of IL-10 are susceptible to certain types of persistent infections because they can't mount appropriate inflammatory responses. If there's an under-abundance of IL-10, they are susceptible to immunopathology caused by collateral damage from the excessive immune response. In this scenario, the original infections clear, but the animals' inflammatory responses set them up for autoimmune diseases and cancers. Animals whose IL-10 gene has been knocked out have extremely compromised anti-inflammatory responses. For example, under conditions that mimic septic shock, 100 percent die within 48 hours due to the cytokine storm, Bream says.
"One of the main roles of IL-10 is to control expression of pro-inflammatory cytokines," Bream explains. "That's how it tries to right the ship, by reducing inflammation to acceptable levels."
If inflammation, which dictates how we respond to vaccines and infectious pathogens, is not under stringent genetic control, the result is disease.
"In terms of public health, I see all these diseases—from heart disease to autoimmune disease to cancer to schizophrenia—as gene regulation issues, related to inflammation," he says. "Some people who get influenza end up hospitalized and die while others recover. Some people get colds and can go to work while others are bedridden. It's this diversity in the human population of response to disease threats that is at the center of my research program."
"When there's imbalance in one thing, it's like a wave that pushes on other things and you get a whole cluster of effects." —Josef Coresh
To find out why some individuals control inflammation better than others, he's looking at tiny genetic variations (known as single nucleotide polymorphisms, or SNPs) that make each human a unique individual, and noting how they affect the levels of IL-10 in various tissues, ultimately exerting control over inflammation and disease.
Because he wants to know how IL-10 works in people, Bream has inserted chunks of DNA containing the human IL-10 gene into the mice he's using. Some mice get human genes with variations associated with high IL-10 expression, and some get human genes with variations associated with low IL-10 expression.
Among other things, he's discovered that location is all-important: Where he manipulates IL-10—that is, which tissue type—matters. If, for instance, Bream turns down the IL-10-producing ability of a subset of cells in a very specific area of the colon, just below the surface cell layer, those mice end up with severe colitis.
"IL-10 is an attractive target for therapeutic interventions that either add back or neutralize IL-10," says Bream, who's now testing different expression levels of the human gene across various tissue types in response to different kinds of infectious pathogens in mice. "By identifying the triggers and genetic variations that regulate IL-10 levels, it will be feasible to develop more personalized therapies that restrict or enhance IL-10 in tissues where inflammation is occurring. But it's extremely complicated."
Another group of researchers at the Bloomberg School is looking at the anti-inflammatory IL-10 cytokine in the context of frailty in older adults. Some elderly people get frail in a clinical sense, meaning they spiral into a vicious cycle of decline characterized by exhaustion, slowness, weakness and muscle loss.
"It's hypothesized that there's at least a subset of older adults in whom inflammation essentially gets turned on all the time," says Karen Bandeen-Roche, PhD, the Frank Hurley and Catharine Dorrier Professor and Chair of Biostatistics, and co-principal investigator of the Older Americans Independence Center. "It's associated with muscle wasting and other adverse outcomes."
Bandeen-Roche is collaborating with Jeremy Walston, MD, a Johns Hopkins professor of Medicine and co-director of the Biology of Healthy Aging Program, who has developed a frail mouse model by knocking out expression of the IL-10 gene.
"In human studies, again and again, associations of high inflammation and adverse outcomes have been revealed, with frailty prominently among them," says Bandeen-Roche. "Pro-inflammation is thought by many to be one of the key hallmarks in a cycle of multisystem dysregulation that leads to frailty."
Human studies designed to discover how inflammation works and reveal its links to diseases require not only big funding and endless approvals but also plenty of participants, willing subjects who are healthy, as well as those who are sick.
People like Patricia Mabe, for instance.
Five years ago, Mabe visited her doctor complaining of asthma-like symptoms. Disconcerting as that was, it didn’t affect her everyday life. An inhaler was prescribed, and for a while, she used it only occasionally. Then, two years ago, it was like a switch had flipped.
“I was always very active—some people might say hyper,” she says. “Then, all of a sudden, I didn’t have any energy.”
An avid walker, Mabe grew depressed when she couldn’t exercise with Buddy, her Yorkshire terrier, and Holly, her English bulldog. Already petite, she lost weight, falling to an alarming 86 pounds.
Quite a few members of Mabe’s extended family had breathing issues. Her parents, both lifelong smokers, needed course after course of antibiotics to fight recurring infections before they died, one year apart, from chronic obstructive pulmonary disorder (COPD). Given her heredity and behavior—despite attempts to quit, Mabe still smokes—she envisioned a bleak future. COPD is an umbrella term that includes chronic bronchitis, emphysema and chronic asthma or asthmatic bronchitis. Most people have a little of this, a little of that, according to Robert Wise, MD, a Johns Hopkins School of Medicine professor of Pulmonary and Critical Care Medicine who holds a joint appointment in EHS at the Bloomberg School. All suffer declining lung function that can contribute to coughing, panic and death. COPD has no cure. Although smoking is a major risk factor, only one in seven smokers ends up with the disease.
Why Mabe’s parents? Why her?
Eager for answers, Mabe signed up for a research study investigating the link between genetics and COPD. More recently, she participated in a clinical trial instigated by Shyam Biswal’s research involving a new therapeutic agent: sulforaphane, a compound from broccoli sprout extract that was discovered in 1992 by Paul Talalay, MD, a professor in Pharmacology and Molecular Sciences who has a joint appointment in International Health at the Bloomberg School.
If scientists can prove in this study and successive clinical trials that sulforaphane works in people—like they previously demonstrated it worked in mice and in human cells in a dish—they will have found a potent intervention for a largely ignored public health issue affecting millions of Americans. (COPD is the No. 3 cause of death nationwide.) In addition, billions of people worldwide also might stand to benefit, mostly women and children whose lungs are chronically compromised from indoor air pollution caused by cooking fires fueled by cow dung and brush.
“Our discovery is not restricted to lung diseases only. If this pans out, it could be a big thing for public health.” —Shyam Biswal
Sulforaphane works differently than existing anti-inflammatory agents, Biswal explains. Rather than tamp down inflammation by interfering with its various pathways, it ramps up a host’s defense system that’s been compromised by chronic inflammation. It breathes new life into Nrf2, a vital molecular player that’s effectively strangled by the “bad” inflammation that underpins not only COPD but also nearly every chronic disease imaginable.
Already, Biswal’s group has published research demonstrating in the lungs of COPD patients that a defect in the host defense results from a decrease in Nrf2. Additionally, they have shown that sulforaphane boosts Nrf2 levels and this enhances host defense in the lungs by improving the ability of macrophages to kill bacteria and making them more responsive to anti-inflammatory drugs such as steroids.
The ongoing clinical trial in which Mabe participated is double-blind, meaning that nobody knows yet whether their purple pills are placebos or contain high or low doses of broccoli sprout extract. But Mabe has a sneaking suspicion that she ingested sulforaphane and that it helped her. During the month-long trial when she dutifully swallowed her pills daily, she felt different. “It seemed like my air passages opened up more,” she reports. “I didn’t have any flare-ups during that time, and it’s odd that I wasn’t on my nebulizer for a whole month.”
The multicenter trial, coordinated here at Johns Hopkins and taking place at Temple University and SUNY Buffalo, to date has enrolled about half of the 90 participants needed to test whether feeding sulforaphane to people alters Nrf2 activity as assessed by anti-oxidant enzymes in macrophages. Reducing inflammation is ancillary.
“If we can’t hit this target, then we’ll have to step back and say, well, this works great in mice and in the test tube, but not when people ingest sulforaphane,” says Wise, who’s heading up the broccoli sprout extract clinical trial.
This wouldn’t be the first inflammation-related wonder-compound to fall apart in a human trial. But Wise is confident in the predictive quality of Biswal’s previous research. In addition, others have shown Nrf2 was increased in the nasal tissue of people who eat broccoli sprouts.
“We think if you can show that in the nose, we can show it in the lung,” Wise says.
That this strategy potentially may benefit nonsmokers who have chronic inflammation in the lungs is notable in the context of public health. Not incidentally, the WHO lists indoor air pollution from primitive household cooking fires as the leading environmental cause of death in the world.
“There’s no question that women and children in South America, Africa and South Asia are exposed for many hours a day in cooking huts to amazingly high levels of particulates from burning biofuels like cow dung, and that this leads to a condition that is akin to COPD,” Wise says. “They develop chronic cough and mucus production. They have airflow obstruction and die early.”
How their lungs are similar to or different from those compromised by tobacco-related COPD is unknown, prompting Biswal to remain hot on the Nrf2 trail.
Currently, he’s implanting particulate collected from cooking huts in India into the lungs of mice and testing how manipulations of the Nrf2 pathway affect disease outcomes. Next, he’s working on developing a breathing chamber for mice that would be analogous to the interior of a cooking hut.
“Our understanding is very weak in this area,” Biswal says, “and half the world’s population is at risk.”
If sulforaphane does, in fact, tackle COPD by boosting the defense system and rendering the immune system once again competent, complete with robust macrophages, what’s to prevent it from doing the same for those suffering from a gamut of inflammation-related diseases, including cystic fibrosis, HIV, cancer, asthma, psoriasis, sepsis, schizophrenia, atherosclerosis …?
“Nothing,” says Biswal. “Our discovery is not restricted to lung diseases only. If this pans out, it could be a big thing for public health.”
Utafiti mpya unaonyesha kwamba uvimbe husababisha karibu magonjwa yote ya kudumu. "Patricia Maybe alipumua kwa mara ya kwanza, akifurahia hewa ya Carbondale, Pennsylvania, makao ya mgodi wa kwanza wa chini ya ardhi nchini Marekani, mji ambao bado unawaka moto kutokana na moto wa ""vituo vya makaa ya mawe.""" Mabe alipomvuta dawa za kulevya kabla ya kuanza kuvuta sigara akiwa na umri wa miaka 15, aliona sumu nyingi. Baba yake, ambaye alifanya kazi katika mgodi, alikuwa mvutaji sigareti. Mama yake pia alivuta sigareti. Wakati wowote Mabe anapopumua kitu chochote chenye sumu, mfumo wa ulinzi wa mwili wake unatambua molekuli za kigeni katika mapafu yake kama wavamizi walivyo na huanzisha majibu ya uchochezi. Chembe za mwili zinazoitwa macrophages, pamoja na nyingine, zilivamia mapafu yake ili kuondoa vimelea na mabaki wakati wa kutolewa kwa mtiririko wa wajumbe wa molekuli ambao walipanga vita vya kimkakati na kurekebisha seli zilizoharibiwa. Kisha - na hii ni kila kidogo kama muhimu kama SWAT-timu yao kama kuwasili - macrophages ingekuwa kuondoka na wote wao mbalimbali makombora katika tow mara moja utume ilikuwa juu. Katika mfumo wenye afya, chembe za uvimbe ni zote mbili sana kudhibitiwa na kujidhibiti; wao kwenda ambapo aliamuru, mtaalamu kutofautisha rafiki kutoka adui, kutumia tu muhimu nguvu ya moto, kusafisha baada ya wenyewe na kisha kujiondoa, hatimaye kurejesha utulivu - pia inajulikana kama homeostasis. Ingawa mfumo wa kinga yaweza kuwa sahihi, kiwango fulani cha kujishambulia hutokea hata wakati sehemu zote zikitenda kazi vizuri. Jambo kuu ni kudhibiti uharibifu unaosababishwa na tukio hilo. Kwa kweli, jinsi mtu yeyote anavyoweza kudhibiti uvimbe ni jambo muhimu linaloamua afya na ugonjwa. Watu fulani husimamia uvimbe vizuri kuliko wengine. Inawezekana kwamba wengi wetu tunaweza kudhibiti uvimbe wakati fulani wa maisha yetu vizuri kuliko wakati mwingine. Kwa nini na jinsi gani ni lengo la utafiti wa kuvutia ambayo inaonyesha jinsi lishe na uvimbe huingiliana katika karibu kila ugonjwa mkubwa wa muda mrefu. "Mfumo wa uvimbe ni kama bahari. Ni nzuri, lakini pia ni hatari". "Kuna uwezekano wa kuwa na nafasi wakati sisi ni nzuri katika kukabiliana na nini ni katika mazingira yetu, ambayo ni karibu kuhusiana na jinsi sisi kukutana na kusalimiana na kujilinda kutoka wavamizi uwezekano, ""anasema Keith West, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD, PhD." <unk>Tunapata chini nzuri katika kwamba kama maisha huenda juu. <unk> Baada ya muda <unk> pengine katika majibu ya sumu na kudumu ya moshi wa sigara katika mapafu yake <unk> Mabe <unk> majibu ya uchochezi akageuka pathological. Muundo wa molekuli na chembe za kinga ulibadilika kwa ubora na kwa wingi. Uvimbe ulikuwa mwingi sana; ulikuwa mwingi sana; ulikuwa wenye nguvu sana kwa muda mrefu sana. Jambo lililotatanisha zaidi ni kwamba, makrofagi pia hayakufaa na yalidumu katika mapafu yake, yakifunga njia zake za kupumua. Kile kilichokuwa kikimlinda dhidi ya ugonjwa sasa kilikuwa kikisababisha ugonjwa huo. Kuna buzz mpya miongoni mwa wanasayansi kuhusu uvimbe, ingawa imekuwa inajulikana kwa miaka kuwa moja ya majibu ya kwanza na mfumo wa kinga kwa maambukizo na kuchochea. Uvimbe ni moto. Na si tu katika aina ya kawaida ya "kalori". Calor - kama joto au homa - ni mojawapo ya sifa nne za uvimbe zilizoandikwa katika De medicina, maandishi ya kale ya kitiba ya Kiroma. Matatizo matatu yaliyobaki - maumivu, rangi nyekundu na uvimbe - hufanywa kuwa maumivu, mwekundu na uvimbe, kwa mtiririko huo. "Uchungu ni kitu ambacho tumegundua tena katika karne ya 21, ""anaelezea Shyam Biswal, PhD, MS, profesa katika Sayansi ya Afya ya Mazingira (EHS), ""haswa, uvimbe kama kitovu cha ugonjwa sugu.""" Watu waliwahi kuiona kuwa kiashiria cha ugonjwa. "Kama ""mwisho wa kuvutia"" kwa ajili ya matibabu ya ugonjwa wa kuambukiza, ""mwisho wa kuambukiza"" ni Noel Rose, MD, PhD, Mkurugenzi wa Kituo cha Utafiti wa Magonjwa ya Autoimmune." Baada ya kuanzisha wazo la autoimmunity kama sababu ya ugonjwa wa thyroiditis ya muda mrefu mnamo 1956, Rose sasa anachunguza sababu za majibu ya uvimbe ulioongezeka katika mioyo ya vijana ambao kupandikiza ni tiba pekee. Rose anakiri kwamba misuli inayohitaji kusukumwa ni mahali pabaya pa kutokeza makovu mengi kwa sababu ya uvimbe. "Sasa tunaangalia maelezo ya uvimbe", anasema, "na kutambua faida za kulenga sehemu maalum za majibu ya uvimbe. "Ni muhimu kujua ni sehemu gani inayofanya vizuri na ambayo inafanya vibaya na kuandaa dawa ipasavyo.Si tu uwepo au kiasi cha uvimbe ni muhimu, Rose anasema: ""Ni muundo wake; muundo wa seli ambazo huvutiwa, njia ambazo huchochewa na bidhaa zinazotolewa.""" "Kama unavyojua, ""mwisho wa siku"" ni ugonjwa wa atherosclerosis, ambao ni ugonjwa wa damu, na ambao ni ugonjwa wa damu, ""anasema Josef Koresh, MD, PhD, MHS, Mkurugenzi wa Kituo cha Utafiti na Uzuiaji wa Afya ya Umma cha George W. Comstock." "Tumejua kwa muda mrefu kwamba uvimbe ni muhimu kwa atherosclerosis, "anasema Coresh, mtafiti mkuu wa Johns Hopkins Field Center ya Atherosclerosis Hatari katika Jumuiya (ARIC) utafiti. <unk>Unaweza kuona chembe za uvimbe katika vidonda.<unk> (Vidonda vinavyoitwa plaques, hufanyiza vidonda katika mishipa, vikifanya iwe ngumu.) Utafiti wa ARIC, ambao ulichunguza Wamarekani 15,792 mnamo 1987, ni rasilimali muhimu kwa uchunguzi wa magonjwa mengi ya kudumu yanayohusiana na uvimbe, ambayo ni machache ambayo yanaonyesha mikono yao wazi kama atherosclerosis. Watafiti wanaochunguza chanzo cha ugonjwa wa kansa na kisukari, kwa mfano, wamegundua kwamba mara nyingi ugonjwa huo unatokana na uvimbe. "Kwa hivyo, ""mchanganyiko wa maambukizo yaliyotatuliwa na kuonekana kuwa hayana uhusiano na maambukizo yaliyofunikwa ndani ya wakati uliopita wa watu, yanaweza kuathiri usawa wa mfumo wa kinga, bila kuonekana ikiwa haibadiliki kabisa.""" Kwa mfano, huenda ugonjwa wa uvimbe unaosababishwa na mafuta mengi mwilini ukaendelea kuwaka. Utafiti huo unazingatia kugundua njia ambazo zilihusianisha maambukizo na uvimbe na baadaye magonjwa ya kudumu. "Kama ilivyoelezwa hapo juu, ""kuchunguza na kurekebisha michakato ambayo inaweza kuzuia, kuongeza au vinginevyo kudhibiti uvimbe mara timu ya SWAT imepigana.""" Si tu uwepo au kiasi cha uvimbe ni muhimu. Ni muundo wake. "Kwa mfano, Andy Pecos, PhD, na washirika kutoka Johns Hopkins Medicine, wameonyesha kwamba seli za epithelial zilizokusanywa kutoka pua za wagonjwa wanaosumbuliwa na sinusitis ya muda mrefu ""kumbuka"" vizazi vingi baadaye kwamba ni tofauti." Chembe hizi zimeongeza majibu ya uchochezi kwa vichocheo mbalimbali mwezi mmoja baada ya kuondoka mazingira ya pua yenye ugonjwa - licha ya kukua na kuenea chini ya hali sawa na seli zenye afya katika sahani za utamaduni wa maabara. "Hii inatuambia kuna kitu kuhusu seli hizi ambayo imebadilika", anaelezea Pekosz, profesa msaidizi katika Idara ya W. Harry Feinstone ya Molecular Microbiology na Immunology (MMI). "Mashine ya kugundua au mzunguko katika seli kutoka kwa wagonjwa wa sinusitis hupangwa upya ili kujibu tofauti kwa sababu zinazosababisha uvimbe. ""Kuelewa programu hii ya kujibu uvimbe yenyewe ni grail takatifu kwa Pekosz." "Ikiwa tunaweza kuelewa jinsi ya kupunguza mwitikio huo wa juu wa chembe za epithelial, tunaweza kupunguza sinusitis sugu", anasema. "Ukizingatia kwamba, ikiwa tunaweza, kwa wakati unaofaa na mapema, kupata njia ya kuongeza majibu ya uchochezi, tunaweza kuwa na chombo kikubwa sana cha kutumia dhidi ya virusi kadhaa tofauti, kwa mfano, ""Kuchanganya hata kidogo na sehemu yoyote ya mfumo dhaifu na tata sio bila matokeo yasiyotazamiwa, ambayo mengi yanaweza kuwa hatari, ikiwa sio mara moja, basi wakati mwingine katika siku zijazo." "Hata hivyo, dawa ya ""Vioxx"" ambayo ni dawa ya kuzuia uvimbe, iliondolewa soko mwaka 2004 baada ya utafiti kuonyesha kuwa dawa hiyo iliongeza mara mbili hatari ya kupatwa na mshtuko wa moyo baada ya miezi 18 ya matumizi." Mfumo wa uvimbe ni kama bahari, kulingana na Coresh: "Ni nzuri, lakini pia ni hatari", anasema. "Muda mrefu kama ni utulivu, unaweza kufanya biashara na samaki juu yake, na bila yake, wewe ni wafu". Lakini, ikiwa inapatwa na dhoruba, ni yenye nguvu sana na inaweza kukuua. "Wakati kuna usawa katika kitu kimoja, ni kama wimbi ambalo husukuma vitu vingine na unapata kundi zima la athari. ""Miongoni mwa mambo ambayo husababisha na kuitikia usawa wa mfumo ni protini za mjumbe zinazoitwa cytokines. Mfumo wa kinga huwasiliana kupitia mambo hayo mbalimbali yanayotiririka katika mtiririko wa damu. Tofauti na chembe za neva katika mfumo wa neva uliounganishwa kwa waya, chembe za mfumo wa kinga hazihusiani moja na nyingine kimwili. "Kama mfumo wa neva ni simu ya mkononi, mfumo wa kinga ni simu ya mkononi,"" anasema Jay Bream, PhD, profesa msaidizi wa MMI." "Vipengele mbalimbali vya cytokines, kwa wingi mbalimbali, hutimiza fungu muhimu katika kuamua majibu ya kinga". "Mgogoro wa cytokine unaweza kutokea wakati mfumo wa kinga unapokabiliwa na ""mchanganyiko wa mjumbe"" ambao huamsha seli ambazo zilikuwa zimesababisha ugonjwa huo." Kwa mfano, dhoruba za cytokine zinahusishwa na maambukizo mabaya ya bakteria na mwanzo wa mshtuko wa septic na maambukizi ya homa ya ndege (H5N1). Vivyo hivyo, maambukizi ya virusi vya Ebola vinavyosababisha kifo huhusianishwa na msukosuko wa cytokine unaosababisha uvimbe usioweza kudhibitiwa. Dhoruba za cytokine zaweza kutokea katika tishu kotekote mwilini. Hii ni kwa sababu sehemu za mfumo wa kinga huenea mbali mbali, kutoka kwenye tabaka la juu la ngozi hadi kwenye sehemu za ndani zaidi za matumbo. "Briam, ambaye kazi yake ni kuunganisha cytokines na matokeo ya ugonjwa, anajifunza Interleukin-10 (IL-10): ""Lynchpin"" anasema, ""katika nexus ya uvimbe.""" Wakati kiasi cha IL-10 kinapungua, uvimbe hutokea. Wakati ni blasting, uchochezi ni tamped chini. "Briam, mkurugenzi mwenza wa Becton Dickinson Immunophilic Laboratory katika Chuo cha Bloomberg, ameonyesha kwamba panya wanaosababisha viwango vya juu vya IL-10 wana uwezekano wa kuambukizwa aina fulani za maambukizi ya kudumu kwa sababu hawawezi ""kuweka"" majibu ya uchochezi sahihi." Ikiwa kuna upungufu wa IL-10, wao ni nyeti kwa immunopathology inayosababishwa na uharibifu wa collateral kutoka kwa majibu ya kinga ya kupita kiasi. Katika hali hii, maambukizi ya awali ni wazi, lakini majibu ya uchochezi ya wanyama huweka kwa magonjwa ya autoimmune na kansa. Wanyama ambao jeni la IL-10 limepigwa, wana majibu ya kupambana na uvimbe yaliyoharibiwa sana. "Kwa mfano, chini ya hali zinazofanana na mshtuko wa septic, asilimia 100 hufa ndani ya masaa 48 kutokana na dhoruba ya cytokine, ""alisema Bream." "Kama sehemu ya kazi ya IL-10, IL-10 ina jukumu la kudhibiti ""pro-inflammatory cytokines"" (pro-inflammatory cytokines)." "Hiyo ndiyo njia inayojaribu kurekebisha hali, kwa kupunguza uvimbe hadi kiwango kinachokubalika". Kama uvimbe, ambao huamua jinsi tunavyokabiliana na chanjo na vimelea vinavyosababisha maambukizo, hauko chini ya udhibiti mkali wa maumbile, matokeo ni ugonjwa. "Kwa suala la afya ya umma, naona magonjwa haya yote - kutoka ugonjwa wa moyo hadi ugonjwa wa autoimmune hadi kansa hadi schizophrenia - kama masuala ya udhibiti wa jeni, yanayohusiana na uvimbe", anasema. "Watu fulani wanaopata mafua huishia hospitalini na kufa huku wengine wakipona. Watu fulani hupata homa na wanaweza kwenda kazini huku wengine wakiwa wamelala kitandani. "Ni tofauti hii katika idadi ya watu ya majibu ya vitisho vya magonjwa ambayo ni katikati ya programu yangu ya utafiti. """ "Wakati kuna usawa katika kitu kimoja, ni kama wimbi ambalo husukuma vitu vingine na unapata kundi zima la athari". "Josef Koresh, mwanasayansi wa magonjwa ya akili, anasema: ""Kuweka kinga ya uvimbe kwa watu fulani ni muhimu kwa sababu kuna tofauti ndogo za maumbile (simple nucleotide polymorphisms, SNPs) ambazo hufanya kila mtu awe mtu wa kipekee, na kutambua jinsi zinavyoathiri viwango vya IL-10 katika tishu mbalimbali, hatimaye kudhibiti uvimbe na ugonjwa.""" Ili kujua jinsi IL-10 inavyofanya kazi kwa binadamu, Bream ameweka vipande vya DNA vyenye jeni la IL-10 katika panya. Panya wengine hupata jeni za binadamu na tofauti zinazohusiana na uonyesho wa juu wa IL-10, na wengine hupata jeni za binadamu na tofauti zinazohusiana na uonyesho wa chini wa IL-10. "Kati ya mambo mengine, amegundua kwamba eneo ni muhimu sana: ambapo yeye manipulates IL-10 ""yaani, ambayo aina ya tishu"" masuala." Kwa mfano, ikiwa Bream inakataza uwezo wa kutengeneza IL-10 katika sehemu fulani ya seli katika sehemu fulani ya tumbo, chini ya safu ya seli za juu, panya hao wanapata ugonjwa mbaya wa uvimbe. "IL-10 ni lengo la kuvutia kwa uingiliaji wa matibabu ambayo ama huongeza au kutofautisha IL-10,"" anasema Bream, ambaye sasa anajaribu viwango tofauti vya kujieleza kwa jeni la binadamu katika aina mbalimbali za tishu katika majibu ya aina tofauti za vimelea vya kuambukiza katika panya." "Kwa kutambua vichocheo na tofauti za maumbile ambazo zinadhibiti viwango vya IL-10, itakuwa rahisi kuendeleza matibabu ya kibinafsi zaidi ambayo hupunguza au kuongeza IL-10 katika tishu ambazo uvimbe unatokea. """ Lakini ni jambo gumu sana". Watafiti wa Bloomberg School wanaangalia cytokine ya IL-10 ya kupambana na uvimbe katika muktadha wa udhaifu kwa watu wazima wazee. Watu wazee wanakuwa dhaifu katika maana ya kliniki, ikimaanisha kuwa wanaingia katika mzunguko mbaya wa kupungua kwa sifa ya uchovu, polepole, udhaifu na kupoteza misuli. "Kuna uwezekano kwamba kuna angalau sehemu ya watu wazima wazee ambao uvimbe huwasilishwa wakati wote, ""Karen Bande-Roche, Ph.D., Profesa wa Biostatistics wa Frank Hurley na Catharine Dorrier, na mtafiti mwenza mkuu wa Kituo cha Uhuru cha Wazee wa Amerika anasema." "Hii huhusianishwa na kupoteza misuli na matokeo mengine mabaya". Bandeira-Roche ameshirikiana na Jeremy Walston, profesa wa dawa wa Johns Hopkins na mkurugenzi mwenza wa Biolojia ya Programu ya Kuzeeka kwa Afya, ambaye amebuni mfano dhaifu wa panya kwa kuondoa usemi wa jeni la IL-10. "Katika masomo ya binadamu, mara kwa mara, ushirika wa uvimbe wa juu na matokeo mabaya yamefunuliwa, na udhaifu unaojulikana kati yao", anasema Bandeen-Roche. "Wengi hufikiri kwamba kuchochea uvimbe ni mojawapo ya sifa kuu katika mzunguko wa kasoro za mfumo mbalimbali zinazoongoza kwenye udhaifu". """Utafiti wa binadamu ulioundwa kugundua jinsi uvimbe unavyofanya kazi na kufunua uhusiano wake na magonjwa unahitaji sio tu fedha nyingi na idhini zisizo na mwisho, lakini pia washiriki wengi, wagonjwa wenye nia, na wale ambao ni wagonjwa." Kwa mfano, watu kama vile Patricia Mabe. Miaka mitano iliyopita, Mabe alimtembelea daktari wake akilalamika juu ya dalili kama za pumu. Ingawa hilo lilimshtua, halikuathiri maisha yake ya kila siku. Alipewa dawa ya kupumua, na kwa muda fulani, alitumia dawa hiyo mara kwa mara tu. Kisha, miaka miwili iliyopita, ikawa kana kwamba kubadili kulikuwa kumetokea. "Sikuzote nilikuwa na shughuli nyingi sana" watu fulani wanaweza kusema hyper, "anasema. "Basi, kwa ghafula, sikuwa na nishati yoyote". "Mabe, ambaye ni mtembeaji mwenye shauku, alishuka moyo aliposhindwa kufanya mazoezi na Buddy, mbwa wake wa Yorkshire, na Holly, mbwa wake wa Kiingereza. Baada ya hapo, alipoteza uzito wake na kufikia uzito wa pauni 86! Washiriki kadhaa wa familia ya Mabe walikuwa na matatizo ya kupumua. Wazazi wake, ambao walikuwa wavutaji wa sigareti kwa muda mrefu, walihitaji dawa za kuua viini ili kupambana na maambukizo yaliyorudiwa-rudiwa kabla ya kufa, kwa tofauti ya mwaka mmoja, kutokana na ugonjwa wa mapafu usio na utaratibu (COPD). Kwa kuzingatia urithi wake na tabia - licha ya majaribio ya kuacha, Mabe bado huvuta - aliona siku zijazo zenye giza. COPD ni neno la jumla linalojumuisha bronchitis ya muda mrefu, emphysema na pumu ya muda mrefu au bronchitis ya pumu. "Watu wengi wana kidogo ya hii, kidogo ya hiyo, kulingana na Robert Wise, MD, profesa wa Johns Hopkins School of Medicine wa Pulmonary na Critical Care Medicine ambaye ana uteuzi wa pamoja katika EHS katika Shule ya Bloomberg. """ Wote wanateseka kutokana na kupungua kwa utendaji wa mapafu ambayo yaweza kusababisha kikohozi, hofu na kifo. COPD haipatikani. Ingawa kuvuta sigareti ni jambo kubwa linaloweza kusababisha ugonjwa huo, ni mmoja tu kati ya watu saba wanaovuta sigareti anayepatwa na ugonjwa huo. Kwa nini wazazi wa Mabe? Kwa nini yeye? Kwa kuwa Mabe alikuwa na hamu ya kupata majibu, alijiunga na utafiti uliochunguza uhusiano kati ya chembe za urithi na ugonjwa wa COPD. Shyam Biswal, ambaye amekuwa akifanya utafiti wa matibabu kwa muda mrefu, amegundua sulforaphane, kiungo kutoka kwa broccoli, ambayo iligunduliwa na Paul Talalay, profesa wa Farmakolojia na Sayansi ya Molekuli, katika Chuo Kikuu cha Bloomberg. "Ikiwa wanasayansi wanaweza kuthibitisha katika utafiti huu na majaribio ya kliniki ya mfululizo kwamba sulforaphane inafanya kazi kwa watu, kama walivyoonyesha hapo awali, ilifanya kazi kwa panya na kwa seli za binadamu katika sahani, watakuwa wamepata uingiliaji wenye nguvu kwa suala la afya ya umma ambalo limepuuzwa sana na kuathiri mamilioni ya Wamarekani. """ COPD ni ugonjwa wa kawaida. 3 sababu ya kifo nchini kote.) Kwa kuongezea, mabilioni ya watu ulimwenguni kote wanaweza pia kufaidika, hasa wanawake na watoto ambao mapafu yao yanadhoofika kwa muda mrefu kutokana na uchafuzi wa hewa wa ndani unaosababishwa na moto wa kupikia unaoendeshwa na chafu ya ng'ombe na msitu. <unk>Ugunduzi wetu haukuhusishi tu magonjwa ya mapafu. "Kama hii itatengenezwa, inaweza kuwa jambo kubwa kwa afya ya umma. ""Shyam Biswal Sulforaphane inafanya kazi tofauti na mawakala wa kupambana na uvimbe waliopo, Biswal anaelezea." Badala ya kupunguza uvimbe kwa kuingilia njia zake mbalimbali, huongeza mfumo wa ulinzi wa mwenyeji ambao umeharibiwa na uvimbe wa kudumu. "Hii inatoa maisha mapya kwa NrF2, mchezaji muhimu wa molekuli ambayo kwa ufanisi hufichwa na ""uchochezi mbaya"" ambao unategemea sio tu COPD lakini pia karibu kila ugonjwa wa muda mrefu unaoweza kuwaziwa." Kwa mujibu wa utafiti uliofanywa na Biswal, ugonjwa wa COPD unaathiri mfumo wa kinga ya mwili wa mtu na hivyo kuathiri uwezo wa mwili wa mtu wa kuhifadhi damu. Sulforaphane huongeza viwango vya NrF2 na hii huongeza ulinzi wa mwenyeji katika mapafu kwa kuboresha uwezo wa macrophages kuua bakteria na kuwafanya wawe na majibu zaidi kwa dawa za kupambana na uvimbe kama vile steroids. Majaribio ya kliniki ambayo Mabe alishiriki ni ya kipofu mara mbili, ikimaanisha kwamba hakuna mtu anayejua ikiwa dawa zao za zambarau ni placebo au zina kipimo cha juu au cha chini cha dondoo la broccoli. Lakini Mabe ana shaka ya siri kwamba yeye kumeza sulforaphane na kwamba alisaidia yake. Wakati wa jaribio la mwezi mmoja alipomeza dawa zake kila siku kwa bidii, alihisi tofauti. "Ilikuwa kana kwamba njia zangu za kupumua zilifunguka zaidi", yeye aripoti. "Hakuna dalili za ugonjwa huo wakati huo, na ni ajabu kwamba sikuchukua dawa ya dawa ya ""nibulizer"" kwa mwezi mzima. jaribio la kituo cha multicenter, lililoandaliwa hapa Johns Hopkins na kufanyika katika Chuo Kikuu cha Temple na SUNY Buffalo, hadi sasa limejiunga na karibu nusu ya washiriki 90 waliohitajika kupima kama kulisha watu sulforaphane hubadilisha shughuli ya Nrf2 kama inavyochunguzwa na enzymes za antioxidant katika macrophages. """ Kupunguza uvimbe ni jambo la ziada. "Ikiwa hatuwezi kufikia lengo hili, basi tutalazimika kurudi nyuma na kusema, ""Hii inafanya kazi vizuri katika panya na katika bomba la majaribio, lakini si wakati watu wanakula sulforaphane,"" anasema Wise, ambaye anaongoza jaribio la kliniki la dondoo la broccoli". Hii haingekuwa mara ya kwanza ya kuambukizwa-kuhusiana ajabu-kiunganishi kuanguka mbali katika majaribio ya binadamu. Lakini Wise ana uhakika katika ubora wa utabiri wa utafiti wa awali wa Biswal. Kwa kuongezea, wengine wameonyesha Nrf2 iliongezeka katika tishu ya pua ya watu wanaokula miche ya broccoli. "Tunafikiri ikiwa unaweza kuonyesha hilo katika pua, tunaweza kuonyesha hilo katika mapafu", anasema Wise. Kwa kuwa mbinu hii inaweza kuwa na faida kwa wasio wavutaji ambao wana uvimbe wa muda mrefu katika mapafu ni muhimu katika muktadha wa afya ya umma. WHO inaorodhesha uchafuzi wa hewa wa ndani kutoka kwa moto wa kupikia wa nyumbani kama sababu kuu ya mazingira ya kifo ulimwenguni. "Hakuna shaka kwamba wanawake na watoto katika Amerika ya Kusini, Afrika na Asia Kusini wanakabiliwa kwa saa nyingi kwa siku katika vibanda vya kupikia kwa viwango vya juu vya chembe kutoka kwa kuchoma biofuels kama mbolea ya ng'ombe, na kwamba hii inaongoza kwa hali ambayo ni sawa na COPD. """ <unk>Hawapatwa na kikohozi cha kudumu na kutokeza umajimaji. "Wana ugonjwa wa kupumua na kufa mapema, ""Biswal alisema, ""Hatujui jinsi mapafu yao yanavyofanana au tofauti na wale walioharibiwa na COPD inayohusiana na tumbaku, na hivyo Biswal anaendelea kuwa moto kwenye njia ya Nrf2.""" Hivi sasa, anaweka chembechembe zilizokusanywa kutoka kwa vibanda vya kupikia nchini India kwenye mapafu ya panya na kupima jinsi udhibiti wa njia ya NrF2 unavyoathiri matokeo ya ugonjwa. Baadaye, anafanya kazi ya kutengeneza chumba cha kupumua kwa panya ambacho kingefanana na sehemu ya ndani ya kibanda cha kupikia. "Biswal anasema, ""Ufahamu wetu ni dhaifu sana katika eneo hili, na nusu ya idadi ya watu duniani iko katika hatari.""Ikiwa sulforaphane inafanya, kwa kweli, kushughulikia COPD kwa kuongeza mfumo wa ulinzi na kufanya mfumo wa kinga tena uwezo, kamili na macrophages imara, nini kuzuia kufanya hivyo kwa wale wanaoteseka kutoka gamut ya magonjwa yanayohusiana na uvimbe, ikiwa ni pamoja na cystic fibrosis, HIV, kansa, pumu, psoriasis, sepsis, schizophrenia, atherosclerosis...?" "Hakuna kitu", anasema Biswal. <unk>Ugunduzi wetu haukuhusishi tu magonjwa ya mapafu. Ikiwa hii itafanikiwa, inaweza kuwa jambo kubwa kwa afya ya umma. <unk>