key: cord-0204577-q1au3azf
authors: Hu, Wan-Chung
title: Acute Respiratory Distress Syndrome is a TH17-like and Treg immune disease
date: 2013-11-18
journal: nan
DOI: nan
sha: 6cb78069db9c79322b2469ca340468d6e8b62038
doc_id: 204577
cord_uid: q1au3azf

Acute Respiratory Distress Syndrome (ARDS) is a very severe syndrome leading to respiratory failure and subsequent mortality. Sepsis is one of the leading causes of ARDS. Thus, extracellular bacteria play an important role in the pathophysiology of ARDS. Overactivated neutrophils are the major effector cells in ARDS. Thus, extracellular bacteria triggered TH17-like innate immunity with neutrophil activation might accounts for the etiology of ARDS. Here, microarray analysis was employed to describe TH17-like innate immunity-related cytokine including TGF-{beta} and IL-6 up-regulation in whole blood of ARDS patients. It was found that the innate TH17-related TLR1,2,4,5,8, HSP70, G-CSF, GM-CSF, complements, defensin, PMN chemokines, cathepsins, Fc receptors, NCFs, FOS, JunB, CEBPs, NFkB, and leukotriene B4 are all up-regulated. TGF-{beta} secreting Treg cells play important roles in lung fibrosis. Up-regulation of Treg associated STAT5B and TGF-{beta} with down-regulation of MHC genes, TCR genes, and co-stimulation molecule CD86 are noted. Key TH17 transcription factors, STAT3 and ROR{alpha}, are down-regulated. Thus, the full adaptive TH17 helper CD4 T cells may not be successfully triggered. Many fibrosis promoting genes are also up-regulated including MMP8, MMP9, FGF13, TIMP1, TIMP2, PLOD1, P4HB, P4HA1, PDGFC, HMMR, HS2ST1, CHSY1, and CSGALNACT. Failure to induce successful adaptive immunity could also attribute to ARDS pathogenesis. Thus, ARDS is actually a TH17-like and Treg immune disorder.

Acute respiratory distress syndrome (ARDS) is a severe cause of respiratory failure.

Despite of current treatment, the mortality rate remains very high. We still don't have successful management strategies to deal with ARDS. Most important of all, we still don't know the exact pathophysiology of ARDS. Sepsis or bacteremia is the leading cause of ARDS. Besides, neutrophil activation is reported in many studies in the lungs of ARDS patients. It was hypothesized that extracellular bacteria-induced TH17 immunity overactivation might be the etiology of ARDS. Microarray analysis to will be used to study the immune-related gene profiles in peripheral leukocytes of ARDS patients.

According to Harrison's internal medicine, the time course of ARDS can be divided into three stages.(1) First, the exudative phase. In this phase, injured alveolar capillary endothelium and type I pneumocytes cause the loss of tight alveolar barrier.

Thus, edema fluid rich in protein accumulate in the interstitial alveolar spaces. It has been reported that cytokines (IL-1, IL-6, and TNF-α) and chemokines (IL-8, and leukotriene B4) are present in lung in this phase (2, 3) . A great numbers of neutrophils traffic into the pulmonary interstitium and alveoli. (4, 5) Alveolar edema predominantly leads to diminished aeration and atelectasis. Hyaline membranes start to develop. Then, intrapulmonary shunting and hypoxemia develop. The situation is even worse with microvascular occlusion which leads to increasing dead space and pulmonary hypertension. The exudative phase encompasses the first seven days of disease after exposure to a precipitating ARDS risk factor such as sepsis, aspiration pneumonia, bacterial pneumonia, pulmonary contusion, near drowning, toxic inhalation injury, severe trauma, burns, multiple transfusions, drug overdose, pancreatitis, and post-cardiopulmonary bypass.

Second, proliferative phase. This phase usually lasts from day 7 to day 21. Although many patients could recover during this stage, some patients develop progressive lung injury and early change of pulmonary fibrosis. Histologically, this phase is the initiation of lung repair, organization of alveolar exudates, and a shift from a neutrophil to a lymphocyte dominant pulmonary infiltrate. There is a proliferation of type II pneumocytes which can synthesize new pulmonary surfactants. They can also differentiate into type I pneumocytes. In addition, there is beginning of type III procollagen peptide presence which is the marker of pulmonary fibrosis.

Third, fibrotic phase. Although many patients with ARDS recover lung function three weeks after the initial lung injury, some enter a fibrotic phase that may require long term support on mechanical ventilators. Histologically, the alveolar edema and inflammatory exudates in early phases are converted to extensive alveolar duct and interstitial fibrosis. Intimal fibroproliferation in the pulmonary microvascular system leads to progressive vascular occlusion and pulmonary hypertension.

According to Dr. J. A. Howrylak's research in Physiol Genomics 2009, who collected total RNA from whole blood in sepsis and sepsis-induced ARDS patients. ( Then, Genespring XI software was done to analyze the significantly expressed genes between ARDS and healthy control leukocytes. P value cut-off point is set to be less than 0.05. Fold change cut-off point is >2.0 fold change. Benjamini-hochberg corrected false discovery rate was used during the analysis. Totally, a genelist of 3348 genes was generated from the HGU133A2.0 chip with 18400 transcripts including 14500 well-characterized human genes.

Dr. J. A. Howrylak performed real time PCR for selected transcripts (cip1, kip2) by using TaqMan Gene Expression Assays (Applied Biosystems, Foster City, CA). In the second dataset, Dr. Melissa Rotunno also performed qRT-PCR test to validate the microarray results. RNA quantity and quality was determined by using RNA 600

LabChip-Aligent 2100 Bioanalyzer. RNA purification was done by the reagents from Qiagen Inc. All real-time PCRs were conducted by using an ABI Prism 7000 Sequence Detection System with the designed primers and probes for target genes and an internal control gene-GAPDH. This confirms that their microarray results are convincing compared to RT-PCR results.

The RMA analysis was performed for RNA samples from whole blood of healthy control of the lung adenocarcinoma dataset. Raw boxplot, NUSE plot, RLE value plot, RLE-NUSE multiplot, and RLE-NUSE T2 plot were generated. Then, sample was included and excluded by using these graphs ( Figure 1A , 1B, 1C, 1D, 1E). Because of the strong deviation in the T2 plot, the sample GSM506435 was removed for the further analysis.

The RMA analysis was performed for RNA samples from whole blood of healthy control of the ARDS dataset. Raw boxplot, NUSE plot, RLE value plot, RLE-NUSE multiplot, and RLE-NUSE T2 plot were generated. Then, sample was included and excluded by using these graphs (Figure 2A , 2B, 2C, 2D, 2E) TH17-like innate immunity and Treg-related genes are up-regulated in ARDS Based on the microarray analysis, we found out that many TH17-related genes are up-regulated in ARDS including Toll-like receptors 1,2,4,5,8, complement, heat shock protein 70, cathpesin, S100A proteins, leukotrienes, defensins, TH17-related chemokines, and MMPs. Many fibrosis related genes are also up-regulated including key collagen synthesis enzymes and fibroblast growth factor. Key TH17 initiating cytokines including TGF beta and IL-6 are also up-regulated. This explains that TH17-like immunity is initiated in ARDS. NK cell and T cell related genes are down-regulated. This explains that TH1 or THαβ immunological pathway is not triggered in ARDS. In addition, TGFB1 and STAT5B up-regulations suggest that Treg cells play important roles in ARDS pathogenesis. (Table 1- 14) In Table 1 , it can be seen that the TLR1, 2,4,5,8 were up-regulated with the expression of IRAK4. Thus, toll-like receptor signaling is generated during ARDS. It is worth noting that TLR1,2,4,5,8 are all anti-bacteria TH17 innate immunity signaling (TLR8 is against CpG rich oligonucleotides). Thus, strong TH17-like related Toll signaling can be activated.

In Table 2 , differentiated expression of heat shock proteins can be seen. Most important of all, HSPA1A, HSPA1B, and HSPA4 are up-regulated. HSPA1A and HSPA1B are greater than 6.0 fold up-regulation. These heat shock proteins are HSP70 family which can activate TH17 related toll-like receptors (TLR2 and TLR4) to generate anti-bacterial immunity. Because of the co-upregulation of TLR2/4 and HSP70, it is evident that the proinflammatory signaling is generated in acute lung injury.

In Table 3 , chemokine and chemokine receptor genes are differentially regulated. TH1 T cell chemotaxis factor CCL5 with its receptor CCR1 and CCL4 with its receptor CCR5 are both down-regulated. TH2 eosinophil chemotaxic factor receptor CCR3 and THαβ NK cell chemotaxic factors XCL1 and XCL2 are all down-regulated. However, TH17-related chemokines such as PAF related molecules and S100A binding proteins are up-regulated. These findings suggest that TH17-like related response to recruit neutrophils is initiated. Toll-like receptor signaling can activate these TH17-like chemokines.

In Table 4 In Table 5 , many immune-related transcription factors are up-regulated or down-regulated. Key Treg related key transcription factor, STAT5B, is up-regulated (8) .

And, THαβ and TH1 related key transcription factor, STAT1, is down-regulated. In addition, TH2 related transcription factor, GATA3, is also down-regulated. Surprisingly, key TH17 transcription factors, STAT3 and RORα, are down-regulated.(9) These findings suggest that full TH17 immunity may not be activated during ARDS. Other innate immunity related genes for myeloid or granulocyte lineages are up-regulated including AP1 (Fos and Jun), CEBP family genes, and NFIL3. It is worth noting that the inhibitor of NFkB, key innate immunity mediator, is down-regulated in acute lung injury. Besides, T cell related transcription factors including NFATC3, NFAT5, and NFATC2IP are down-regulated in ARDS. JAK2, a signal transduction for all cytokines and STATs proteins, is also up-regulated. STAT5B is the key transcription factor for regulatory T cells. And, down-regulation of RORα and STAT3 means only TH17-like innate immunity is activated in acute lung injury.

In Table 6 , it can be seen that many chemotaxic factors, leukotrienes and prostaglandins, are up-regulated or down-regulated. The key enzyme: leukotriene A4 hydrolase for leukotriene B4, a potent PMN chemoattractant, is up-regulated.

Besides, leukotriene B4 receptor is also up-regulated. Furthermore, the receptor of PGD2, a TH2 related effector molecule, is 9 fold down-regulated. In addition, the gene 15-hydroxyprostaglandin dehydrogenase (HPGD), which is responsible for shutting down prostaglandin, is 27 fold up-regulated. Key molecules including phospholipase A 2 and arachidonate 5-lipoxygenase to initiate leukotriene synthesis are also up-regulated in ARDS. And, formyl peptide receptor 2, another chemotaxic receptor of PMN, is also up-regulated. Innate immune initiators, SERPINB1 and SERPINB2, are also up-regulated in acute lung injury.

In Table 7 Heparan sulfate sulfation is a potent stimulation of FGF signaling to cause fibrosis (14, 15) . Hyaluronan-mediated motility receptor (RHAMM) is also up-regulated.

Hyaluronan plays an important role in pulmonary fibrosis. In addition, key collagen synthesis enzymes, prolyl-4-hydroxylases and procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase are also up-regulated in ARDS. (16, 17) In Table 8 , many complement related genes are up-regulated including CD59, C1QB, ITGAM, CR1, C3AR1, ITGAX, C1QA, C1RL, and C5AR1. Complements are important in the TH17 arm to kill extracellular bacteria. Thus, the whole complement machinery is activated in ARDS. In addition, two defensin genes, DEFA1B3 and DEFA4, are also up-regulated to defend the possible bacterial infection. Neutrophil overactivity with up-regulated complements and defensins plays a vital role in acute lung injury.

In Table 9 , many cathepsin genes are up-regulated in acute respiratory distress syndrome including CTSK, CTSG, CTSZ, CTSA, CTSD, and CTSC except CTSO and CTSW.

Cathepsins are important proteases in antigen processing. Thus, antigen processing is likely to be activated in ARDS. However, MHC related genes are down-regulated in acute lung injury. In addition, myeloperoxidase, which is the enzyme responsible for ingested bacteria killing, is upregulated in ARDS. Neutrophil cytosolic factor 1 & 4, the subunit of NADPH oxidase for ingested bacteria killing, are also up-regulated in ARDS.

In Table 10 , two CSF receptors are up-regulated in acute lung injury. CSF2 receptor (GM-CSF receptor) is more than two fold up-regulated. And, CSF3 receptor (G-CSF receptor) is also more than two fold up-regulated. GM-CSF and G-CSF can stimulate granulocyte and monocyte proliferation. It means that myeloid and granulocyte lineages are proliferative in ARDS.

In down-regulated. These findings support that TH17-like armed innate immune response is activated in acute lung injury.

In Table 12 , many TH17-like related cytokine genes are up-regulated in ARDS. Most importantly, the central TH17 cytokine initiators, TGFB1 and IL-6, are up-regulated in ARDS. Thrombospondin (THBS1), the activator of TGFB, is also strongly up-regulated.

In addition, TH22 related cytokines such as IL32 and IL1A are down-regulated. And, IL1RN, an IL1 antagonist, is up-regulated. The receptors of TH17 immunity are also down-regulated, including IL17RA, IL6R, and TGFBR3. The receptors for Treg pathway are also down-regulated, including IL2RB and TGFBR3. However, the key TH17 downstream IL-6/TGFβ inducing transcription factors, STAT3 and RORα, are down-regulated. These findings suggest that only TH17-like innate immunity is up-regulated. Other immunological pathway cytokine receptors are up-regulated, including IL1RA, IL1R2, IL1R1, IL4R, IL18R1, IFNGR1, IFNGR2, IFNAR1, and TNFRSF1A.

Besides, TH1 or THαβ associated interferon related genes are down-regulated, including ISG20L2, IFI16, GVINP1, GBP1, IFI44L, and IFIT3. In addition, FAS is up-regulated and Fas apoptotic inhibitory molecule 3 (FAIM3) is down-regulated.

These findings suggest that apoptosis machinery is activated in ARDS.

In Table 13 , many important CD molecules are differentially regulated. CD molecules are important in mediating host immune reaction. Thus, the up-regulation or down-regulation of these CD molecules suggests the status of host immunity. From this table, we can see that many T cell activation molecules are down-regulated, including CD8A, CD3G, CD3D, and CD86. CD8A is the molecule of cytotoxic T cell activation. CD3G is the molecule for helper or killer T cell activation. CD86 is the key co-stimulation signal to activate B cells and T cells. Thus, the adoptive immunity including B and T lymphocytes are not likely to be activated in ARDS.

In the Table 14 , many NK cells and T cell related molecules are seen to be down-regulated. Molecules related to NK cell activation include grazymes (GZMK, GZMM, GZMB, and GZMH), perforin(PRF1), and killer cell receptors (KLRK1, KLRD1, KLRG1, KLRB1, NKTR, and KLRF1). NKTR is 13-fold down-regulated and granulysin (GNLY) is 5-fold down-regulated. NK cells are the key effector cells in THαβ immunity.

Thus, THαβ immunity is not activated or even down-regulated in ARDS. In addition, many TCR related genes are also down-regulated, including TRBC1, TRAC/J17/V20, TRBC2, TRD@, TRAP/TRGC2, and TRDV3. Several TCR related genes have greater than 5-fold down-regulation. We can see the down-regulations of MHC genes, CD costimulation molecules, STAT3, and TCR genes as well as the up-regulation of TGFB1 and STAT5B. These findings suggest that T cells are not activated in the acute lung injury. Thus, adaptive immunity cannot be successfully triggered in ARDS. Because successful adaptive TH17 helper cells need at least three signals: TGFβ, IL-6, and TCR.

The absence of TCR signal cannot fully trigger TH17 CD4 T cells. Our findings suggest that Treg plays an important role in ARDS pathophysiology.

ARDS is a very severe respiratory complication. Sepsis is the major risk factor of ARDS.

Sepsis is caused by the uncontrolled bacteremia due to bacterial infection. In addition, PMNs overactivation is very important in the pathogenesis of ARDS. Thus, extracellular bacteria induced TH17 immunity with neutrophil activation might be the key in the pathophysiology of ARDS.

Here, I propose a detail pathogenesis to explain the three stages of ARDS. In the first exudative stage, neutrophils are attracted to lung due to chemotaxic agents such as IL-8 or C5 or leukotriene B4. During sepsis, bacterial infection in pulmonary tissue can trigger pulmonary epithelial cells, pulmonary endothelial cells, pulmonary fibroblast, and alveolar macrophage to be activated. Toll-like receptors 1,2,4,5 as well as heat shock proteins (HSP60, HSP70) are key molecules to trigger TH17 host immunity (18) (19) (20) (21) (22) (23) (24) (25) (26) . Heat shock proteins are important stress proteins in situation such as burn, trauma, hemorrhagic shock, near drowning or acute pancreatitis. (27) (28) (29) (33) . First, anti-IL8-IL8 complex can be detected in 55% of healthy control serum. There is no significant difference of IL8-antiI-L8 complex between ARDS patients' serum and healthy controls' serum. In addition, IL8 autoantibody can suppress IL8 binding activity for neutrophils and it can reduce IL8's chemotaxic activity. Thus, IL8 autoantibody's importance in ARDS pathogenesis is doubtful. Bacterial infection is the most common risk factor of ARDS. However, certain pathogens other than bacteria also are risks for developing ARDS. Plasmodium falciparum malarial infection can also cause the complication of ARDS. The reason for this is that Plasmodium falciparum can activate heat shock proteins to trigger TH17 immunity to cause ARDS.(author's paper in press)(48) SARS-CoV and H1N1 Avian flu virus can also down-regulate normal anti-viral interferon-α/β and up-regulate TH17-like immunity to trigger ARDS. (author's paper in press: Viral Immunology)(49, 50) Thus, the above phenomena suggest that TH17 inflammation is the key to the pathogenesis of ARDS. If different pathogens lead to a common pathway of TH17-related innate immunity, they will cause the same consequence of ARDS. It is also seen in burn, trauma, or pancreatitis when TH17-like innate immunity is also activated.

In the second proliferative stage, lymphocytes replace neutrophils and become the dominant population in ARDS. These lymphocytes are TH17-like lymphocytes and Treg lymphocytes. TH17-related cytokines such as IL-17, IL-1, IL-6, and TNF-α can continue the inflammatory process due to the activation of innate immunity.

However, once the bacterial antigen during sepsis is cleared, Toll-like receptor signaling is stopped, and no further proinflammatory cytokines such as IL-6 are synthesized. In addition, there is no TCR signal found in this study. Thus, TH17 adaptive immunity may not be successfully generated. This could be very important in ARDS pathogenesis. In TH17 immunity, both TGF-β and IL-6 are two important triggering cytokines. If there is no longer IL-6 signaling, only TGF-β is generated. IL-6 is the key factor to regulate the balance between Treg cells and TH17 cells. If there is enough IL-6, Treg cells will become TH17 cells. If there is not enough IL-6, TGF-β secreting Treg cells will be maintained. Treg cells are associated with STAT5B activation. Thus, in the third fibrosis stage, TGF-β secreting Treg cells are the dominant effector cells in ARDS. (51) In this study, patients' ARDS is induced by bacterial sepsis. Thus, failure to induce specific adaptive immunity such as TCR and antibody cannot successfully defeat these bacteria. In the early disease stage, overactive innate immunity with PMN activation causes severe lung consolidation. In the later stage, failure of adaptive immunity against bacteria causes the abundant regulatory T cells secreting TGF-β. TGF-β is a very strong fibrosis promoting agent and is the most important and potent stimulant in tissue fibrosis.(52, 53) TGF-β will promote the synthesis of multiple collagen genes.(54) Thus, overproduction of TGF-β in lung tissue will cause pulmonary fibrosis. TGF-β caused fibrosis is usually a process for repairing cavity after bacterial infection locus such as abscess. This mechanism can solve many controversial studies before. Several studies found that TLR4 and heat shock proteins can aggravate ARDS. (20) However, another studies found that TLR4 or heat shock protein can protect from pulmonary fibrosis after acute lung injury. (55) (56) (57) It is because TLR and heat shock signaling can maintain the activation of proinflammatory cytokines such as IL-6. Thus, no sole TGF-β overproduction happens in lung fibrosis. In an animal study, neutrophil inhibitor can attenuate the progression of acute lung injury (58) . Thus, TH17 and Treg inflammatory process can fully explain the pathogenesis of ARDS.

Recently, two researches suggested that Treg cells play protective roles in acute lung injury. (59, 60) We cannot agree with their suggestions. First of all, they used Rag-/mice and found that ARDS is reduced in Rag-/-mice. However, both B cells and T cells are absent in Rag-/-mice. This finding can be explained that adaptive immune T & B lymphocytes relieve the TH17 innate ARDS pathological change. They also found that CD8 T cells have protective roles in ARDS. In this study, we found that antigen specific T cells are not activated in ARDS. Thus, specific TCR or antibody response against bacteria antigen could not be successfully triggered in acute lung injury. If the adaptive immunity can be triggered, it can limit ARDS pathogenesis. Second, they used a lung injury scoring system to assess the severity of ARDS. However, the scoring system only included lung congestion and inflammatory infiltration. The most important sequel of ARDS, pulmonary fibrosis, was not included in their studies. Thus, their conclusion that TGF beta secreting Treg cells can protect ARDS is questionable .

Actually, anti-TGFB antibody can prevent mice from lung fibrosis.(61) After knowing the complete pathophysiology ofARDS, we may be able to develop better treatment strategies to managing this highly detrimental and fatal disease. 

Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients

The expression of hsps, anti-oxidants, and cytokines in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome

Cytokines, genes, and ards

Regulation of neutrophil activation in acute lung injury

Neutrophil activation and acute lung injury

Discovery of the gene signature for acute lung injury in patients with sepsis

A gene expression signature from peripheral whole blood for stage i lung adenocarcinoma

Cutting edge: Decreased accumulation and regulatory function of cd4+ cd25(high) t cells in human stat5b deficiency

lineage differentiation is programmed by orphan nuclear receptors ror alpha and ror gamma

Early elevation of matrix metalloproteinase-8 and -9 in pediatric ards is associated with an increased risk of prolonged mechanical ventilation

Increased deposition of chondroitin/dermatan sulfate glycosaminoglycan and upregulation of beta1,3-glucuronosyltransferase i in pulmonary fibrosis

Carboxypeptidase-mediated enhancement of nitric oxide production in rat lungs and microvascular endothelial cells

Expression of inducible nitric oxide synthase and inflammatory cytokines in alveolar macrophages of ards following sepsis

Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate

Increased responsiveness of hypoxic endothelial cells to fgf2 is mediated by hif-1alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate fgf2-binding sites

Prolyl 4-hydroxylases, key enzymes in the synthesis of collagens and regulation of the response to hypoxia, and their roles as treatment targets

Immunological characterization of lysyl hydroxylase, an enzyme of collagen synthesis

Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide

Hemorrhagic shock-activated neutrophils augment tlr4 signaling-induced tlr2 upregulation in alveolar macrophages: Role in hemorrhage-primed lung inflammation

Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury

Regulation of lung injury and repair by toll-like receptors and hyaluronan

Tlr4 is essential in acute lung injury induced by unresuscitated hemorrhagic shock

Impact of toll-like receptor 4 on the severity of acute pancreatitis and pancreatitis-associated lung injury in mice

Tlr4 gene dosage contributes to endotoxin-induced acute respiratory inflammation

Lipopolysaccharide stimulates syntheses of toll-like receptor 2 and surfactant protein-a in human alveolar epithelial a549 cells through upregulating phosphorylation of mek1 and erk1/2 and sequential activation of nf-kappab

Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced tlr4 pathway in mice

Hsp72 induces inflammation and regulates cytokine production in airway epithelium through a tlr4-and nf-kappab-dependent mechanism

Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury

Burn-induced acute lung injury requires a functional toll-like receptor 4

Bacterial-induced release of inflammatory mediators by bronchial epithelial cells

Pulmonary epithelial cells facilitate tnf-alpha-induced neutrophil chemotaxis. A role for cytokine networking

Differential regulation of cytokine release and leukocyte migration by lipopolysaccharide-stimulated primary human lung alveolar type ii epithelial cells and macrophages

Anti-il-8 autoantibodies in alveolar fluid from patients with the adult respiratory distress syndrome

Interleukin-8 (il-8): The major neutrophil chemotactic factor in the lung

Regulation of interleukin-8 expression in porcine alveolar macrophages by bacterial lipopolysaccharide

Interleukin-8 gene expression in human bronchial epithelial cells

Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung

Human alveolar macrophage gene expression of interleukin-8 by tumor necrosis factor-alpha, lipopolysaccharide, and interleukin-1 beta

Secretory phospholipase a pathway during pediatric acute respiratory distress syndrome: A preliminary study

Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups

Purification and partial primary sequence of a chemotactic protein for polymorphonuclear leukocytes derived from human lung giant cell carcinoma lu65c cells

Tissue-specific mechanisms control the retention of il-8 in lungs and skin

Binding of interleukin-8 to heparan sulfate and chondroitin sulfate in lung tissue

Common features in the onset of ards after administration of granulocyte colony-stimulating factor

Vitamin k3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappab activation

Selective nf-kappab inhibition, but not dexamethasone, decreases acute lung injury in a newborn piglet airway inflammation model

Attenuation of lipopolysaccharide-induced acute lung injury by treatment with il-10

Immunopathology and dexamethasone therapy in a new model for malaria-associated acute respiratory distress syndrome

Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection

Acute respiratory distress syndrome induced by a swine 2009 h1n1 variant in mice

The acute respiratory distress syndrome: A role for transforming growth factor-beta 1

Imatinib mesylate inhibits the profibrogenic activity of tgf-beta and prevents bleomycin-mediated lung fibrosis

Transforming growth factor beta in tissue fibrosis

Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin alphavbeta8-mediated activation of tgf-beta

Tlr4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury

Association between heat stress protein 70 induction and decreased pulmonary fibrosis in an animal model of acute lung injury

Resolution of toll-like receptor 4-mediated acute lung injury is linked to eicosanoids and suppressor of cytokine signaling 3

Neutrophil elastase inhibitor (sivelestat) attenuates subsequent ventilator-induced lung injury in mice

Cd4+cd25+foxp3+ tregs resolve experimental lung injury in mice and are present in humans with acute lung injury

Lymphocytes in the development of lung inflammation: A role for regulatory cd4+ t cells in indirect pulmonary lung injury

Anti-transforming growth factor-beta monoclonal antibodies prevent lung injury in hemorrhaged mice