TABLE 1

Immunomodulatory effects of antibiotics in acute respiratory distress syndrome (ARDS) and lung injury models

AntibioticModelSpecimenStimulants or pathogensImmunomodulatory effectsNeutrophil influxEndothelial permeabilityDegree of lung injurySurvivalReference
MacrolidesAZMHuman (RCT)Nasal and endotracheal samplesRSVMMP-9, IL-1, IL-10, TNF-α (endotracheal) ↓, nasal ⇔NANANANAKong et al. [71]
AZMMouseMacrophages (J774)LPSM2 macrophages (via inhibition of NF-κB STAT1 pathways) ↓NANANANAHaydar et al. [33]
CAMMouseBALF, lung tissue, serumH1N1 influenza virus, S. pneumoniae i.n.IFN-γ ↓, IL-10 ↑
CD11b+Gr-1+ MDSC-like cells (via STAT3 pathway) ↑
NDNDNamkoong et al. [39]
AZMMouseBALF, lung tissueRSV i.n.IL-5, IL-6, IFN-γ ↓NDMosquera et al. [41]
AZMMouseLung tissueH1N1 influenza virus i.n.IL-6, TNF-α ⇔NDNDNDFage et al. [64]
AZMMouseBALF, lung tissue, blood plasmaRadiationIL-1β, IL-6, TNF-α, TGF-β1, α-SMA, COL1A1 ↓, oxidative damage (lipid peroxidation) ↓NDNDNDTang et al. [40]
AZMMouseBALF, lung tissueP. aeruginosa i.t.Caspase-1 activation ↓, IL-1β cleavage ↓
IL-1β, IL-18 ↓
NDFan et al. [30]
AZMHuman (cohort study)Blood plasma, PBMCsH3N2 influenza virusIL-6, CXCL8, IL-17, CXCL9, sTNFR-1, IL-18, IFN-γ, IP-10 ↓NDNDNDNDLee et al. [42]
AZMHuman (cohort study)Blood plasma, BALFCommunity-acquired pneumoniaIL-6, TNF-α (plasma)↓, IL-8, lL-10 (BALF)↓NDNDNDNDLorenzo et al. [70]
CSY0073, AZMMouseBALF, lung tissue, alveolar macrophages, BECLPS i.n.TNF-α, CXCL1, CXCL2, IL-6, IL-1β ↓NDNDNDBalloy et al. [144]
AZMMouseBALFLPS i.t.NF-κB, TNF-α, G-CSF, IL-6, IL-9, MCP-1↓NDNDNDStellari et al. [35]
CAMMouseBALF, lung tissueVentilationNF-κB, E-selectin ↓
MMP-2, MMP-9⇔
NDAmado-Rodríguez et al. [36]
AZMMouseBALF, lung tissueA. baumanii i.b.IL-1β, IL-6, MIP-2, macrophages, lymphocytes ↓NDYamada et al. [48]
CAMHuman (in vitro)Alveolar epithelial cells (A549)RSV, S. pneumoniaeIL-6, IL-8, CCL5/Rantes ↓
PAF receptor expression ↓
NANANANAYokota et al. [51]
CAMHuman (RCT)Monocytes, neutrophilsVentilator-associated pneumoniaIL-6, monocyte apoptosis, CD86, TREM-1↑, TNF-α ↓, restored TNF-α/IL-10 ratioNDNDNDNDSpyridaki et al. [8]
AZMMouseBALF, lung tissue, macrophages (J774)LPS i.n.IL-1β ↓ by inhibition of AP-1 activation, NF-κB, ERK-1 and -2 ⇔NDNDBosnar et al. [31]
AZMMouseBALF, lung tissueP. aeruginosa i.t.TNF-α, IL-6, CCL2↓, IFN- γ, IL-10, IL-12p70 ⇔, M2 macrophages, arginase1, mannose receptor, CD11b+Gr-1+ MDSC-like cells ↑NDNDFeola et al. [38]
CAMMouseBALF, lung tissueH. influenzae i.t.IL-1β, MIP-2 ↓NDNDNakamura et al. [47]
CAMHuman (in vitro)Tracheal epithelial cellsH3N2 influenza virusIL-1β, IL-6, IL-8, NF-κB (p50, p65) ↓NANANANAYamaya et al. [34]
AZM, CAMMouseBALF, lung tissue, macrophages (J774)LPS i.n.MCP-1/CCL2, GM-CSF, IL-1β, TNF-α, E-selectin, MPO concentration↓ CXCL1, CXCL2 ⇔NDNDNDBosnar et al. [43]
CAMMouseBALF, lung tissue, alveolar macrophagesK. pneumoniae i.n.Oxidative damage (NO, MDA, MPO) ↓, macrophage phagocytic activity ↑NDNDKumar et al. [44]
AZMMouseMacrophages (J774)LPSM2 macrophages ↑ (IL-10, IL-23, mannose receptor, CD23 ↑; IL-6, IL-12, CCR7, iNOS ↓)NANANANAMurphy et al. [56]
AZMHuman (ex vivo)PBECLPSIL-8, GM-CSF ↓, VEGF ⇔NANANANAMurphy et al. [49]
EM703MouseBALF, lung tissueBleomycin i.v.TGF-β, macrophages, fibroblasts ↓NDNDLi et al. [62]
AZMMouseLung tissueP. aeruginosa i.t.KC/CXCL1, TNF-α ↓, inhibition of ERK-1 and -2 activationNDNDNDTsai et al. [46]
CAMMouseBALF, lung tissueM. pneumoniae i.n.IFN-γ, TNF-α, IL-6, KC/CXCL1, MIP-1α, MCP-1 ↓NDNDNDHardy et al. [50]
CAM, RXM, AZM, JMMouseBALF, lung tissueBleomycin i.t.KC/CXCL1 ↓ (RXM, CAM), apoptosis of bronchial and alveolar epithelial cells ↓ (RXM>CAM>AZM)↓ (RXM> CAM>AZM), JM ⇔↓ (RXM> CAM>AZM), JM ⇔↓ (RXM> CAM>AZM), JM ⇔NDKawashima et al. [45]
ERMMouseBALF, serum, macrophages (RAW 264.7)H2N2 influenza virus nebulisationIFN-γ, NO metabolites (nitrite, nitrate) ↓, macrophages, lymphocytes ↓NDNDSato et al. [63]
KetolidesTELMouseBALF, macrophages (RAW 264.7), epithelial cells (MLE-12)LPS nebulisationNitrite, MIP-2, TNF-α ↓NDNDLeiva et al [75]
TetracyclinesTETMouse, human (ex vivo)BALF, BMDM; alveolar leucocytesLPS, H1N1 influenza virus i.t. (mouse); viral, bacterial and non-pulmonary ARDS (human)IL-1β, IL-18, caspase-1 activation ↓NDPeukert et al. [9]
DOXMouseLung tissue, blood plasmaCaecal ligation and punctureTNF-α, IL-1β, IL-6, MPO ↓NDNDNDPatel et al [84]
DOXMouseBALF, lung tissue, serumParaquat i.t.MMP-9, MPO ↓NDNDZhang et al. [147]
DOXRatBALF, lung tissue, blood plasmaCardiopulmonary bypassTNF-α, IL-1β, MMP-9 ↓NDNDWang et al. [85]
DOXDogBALF, lung tissue, blood plasmaCardiopulmonary bypassMMP-9, MPO ↓NDZhang et al. [82]
CMT-3PigBALF, lung tissue, blood plasmaIschaemia by clamping of SMA, placement of faecal clot in peritoneumTNF-α, IL-1β, Il-6, IL-8, IL-10 ↓, MMP-2, -9, NE ⇔NDRoy et al. [86]
DOXMouseBALF, lung tissueH3N2 influenza virus i.n.MMP-2, MMP-9, T1-α, thrombomodulin ↓NDNg et al. [91]
DOXMouseBALF, lung tissueLPS i.t.Syndecan-1 (substrate of MMP-7) ↓NDMoon et al. [79]
CMT-3SheepLung tissue, blood plasmaThird-degree burn, smoke inhalation, barotrauma injuriesMMP-2 ↓, MMP-9 ⇔NDNDZhou et al. [94]
DOXRatLung tissueAcute pancreatitis (intraductal glycodesoxycholic acid, cerulein i.v.)MMP-9 ↓NDSochor et al. [80]
DOXMouseBALF, lung tissueLPS or S. pneumoniae i.t.MMP-2, -9 ↓NDFujita et al. [81]
CMT-3RatBALF, lung tissueVentilationMMP-9, MPO ↓NDKim et al. [88]
CMT-3PigBALF, lung tissue, serum, blood plasmaIschaemia by clamping of SMA Placement of faecal clot in peritoneumIL-6, IL-8, IL-10, NE ↓, IL-1, MMP-2, -9 ⇔NDSteinberg et al. [87]
CMT-3RatBALF, lung tissue, serumCaecal ligation and punctureMMP-2, MMP-9 ↓NDSteinberg et al. [78]
CMT-3PigBALF, lung tissueLPS i.v.MMP-2, MMP-9 ↓NDCarney et al. [93]
CMT-3PigLung tissueCardiopulmonary bypass, LPS i.v.NDNDNDNDMcCann et al. [92]
CMT-3PigBALF, lung tissueCardiopulmonary bypass, LPS i.v.MMP-2, NE ↓NDCarney et al. [83]
OxazolidinonesLZDHuman (ex vivo)NeutrophilsC5a, MRSANeutrophil phagocytosis and killing ↑, respiratory burst, neutrophil transmigration ⇔NANANANAEvans et al. [118]
LZDMouseBALFH1N1 influenza virus, MRSA i.n.TNF-α, IL-6 ↓NDVerma et al. [111]
LZDRabbitLung tissue, whole bloodMRSA i.n.TNF-α ↓NDNDNDPauchard et al. [100]
LZDMouseBALF, lung tissue, alveolar macrophagesH1N1 influenza virus i.n., MRSA i.t.KC/CXCL1, MIP-2, IFN-γ, TNF-α, IL-1β ↓NDBhan et al. [110]
LZDHuman (in vitro)THP-1 monocytesLPSTLR-1, -2, -6 ↑, phagocytic activity ↓NANANANABode et al. [114]
LZDMouseLung tissueMRSA t.t.TNF-α, IL-1β, MIP-2 ↓NDJacqueline et al. [97]
LZDMouseBALF, lung tissueMRSA i.n.IL-1β, IL-6, IL-17, IFN-γ ↓NDChen et al. [99]
LZDMouseLung tissueH1N1 influenza virus, MRSA i.n.IFN-γ, KC/CXCL1, IL-6 ↓, IL-1β, TNF-α, IL-12 ⇔NDNDNDNDLiu et al. [109]
LZDMouseBALF, lung tissue, TBLNH1N1 influenza virus, S. pneumoniae i.n.IFN-γ, TNF-α ↓NDNDNDNDBreslow-Deckman et al. [103]
LZDHuman (ex vivo)Whole bloodMRSAIL-6, IL-8, MCP-1 ↓NANANANAFranks et al. [113]
LZDMouseLung tissueMRSA i.n.TNF-α, IL-6, IL-12 ↓NDNDNDNDYoshizawa et al. [101]
LZDMouseBALF, lung tissue, alveolar macrophagesMRSA t.t.MCP-5, IL-6, MMP-9 ↓, neutrophil apoptosis ↑, efferocytosis ⇔NDNDAkinnusi et al. [96]
LZDPigletBALF, lung tissue, serum, blood plasmaMRSA i.t.TNF-α, IL-6 ⇔NDNDLuna et al. [98]
LZDMouseLung tissueMRSA i.v.TNF-α, IL-1β, MIP-2 ↓NDNDYanagihara et al. [148]
LZDHuman (ex vivo)PBMCLPSIL-1β, IL-6, TNF-α, IL-1RA ↓NANANANAGarcia-Rocca et al. [112]
LZDHuman (ex vivo)PMNMRSA, MSSA, VREPhagocytosis, production of superoxide, hydrogen peroxidase radicals ⇔NANANANABallesta et al. [116]
FluoroquinolonesLVFXMurineBALF, lung tissue, bloodH1N1 influenza virus i.t.IFN-γ, TNF-α ↓, oxidative and nitrative stress: NO metabolites, ROS ↓NDNDEnoki et al. [122]
MOXHuman (ex vivo), mouseBALF, lung tissue, blood plasmaS. pneumoniae i.n.IL-6, IL-8, IL-1β, KC/CXCL1 ⇔NDNDMüller-Redetzky et al. [126]
MOXMouseBALF, lung tissue, blood plasmaS. pneumoniae, P. aeruginosa i.n.IL-1β, KC/CXCL1, IL-17A ↓, TNF-α expression in lung tissue ↓NDNDBeisswenger et al. [123]
CPFX, LVFX, MOXMouseBALF, serumLPS i.t.TNF-α, IL-1β, MIP-2 ↓ (CPFX)ND↓ (CPFX), ⇔ LVFX, MOX↓ (CPFX), ⇔ LVFX, MOX↓ (CPFX), ⇔ LVFX, MOXHuang et al. [124]
MOXMouseLung tissueC. albicans i.t., cyclophosphamide i.p.TNF-α, KC/CXCL1 ↓, IL-2, IL-10, IFN-γ ⇔NDNDShalit et al. [125]
Epoxid antibiotic fosfomycinFOMRatLung tissueCaecal ligation and punctureTLR-4, NF-κB, TNF-α, oxidative damage (TBARS ↓, -SH ↑) ↓NDNDNDYildiz et al. [137]
FOMHuman (ex vivo)PMNLPSIL-6 ↓NANANANAUbugai et al. [149]
FOMHuman (in vitro), mouseTHP-1 monocytes, alveolar epithelial cells (MLE-12), lung tissue, BALFS. aureus i.v.MAPK (JNK, ERK, p38), NLRP3 proteins and activation, IL-1β, IL-18, MPO ↓NDAn et al. [138]
FOMHuman (cohort study)Whole bloodLPSTNF-α, IL-1β, IL-6 ⇔NANANANASauermann et al. [142]
FOMHuman (ex vivo)Whole bloodLPSTNF-α, IL-1β, IL-6 ↓, IL-4, IL-10, IL-13 ⇔NANANANAZeitlinger et al. [140]
FOMMouseSerumLPSTNF-α, IL-1β ↓NANANANAMatsumoto et al. [139]
FOMHuman (ex vivo)MonocytesLPSTNF-α, IL-1α, IL-1β, IL-1RA, GM-CSF↓NANANANAMorikawa et al. [141]
FOMHuman (ex vivo)PMNS. aureusPhagocytosis and killing ↑NANANANAPérez Fernández et al. [136]

↑: Significant increase; ↓: significant decrease; ⇔: no significant difference; A.: Acinetobacter; AP: activator protein; AZM: azithromycin; BALF: bronchoalveolar lavage fluid; BEC: bronchial epithelial cell; BMDM: bone marrow derived macrophages; C.: Candida; CAM: clarithromycin; CCL: CC chemokine receptor; CMT-3: chemically modified tetracycline-3; COL1A1: α-1 type I collagen; CPFX: ciprofloxacin; CSY0073: non-antibiotic derivative of AZM; CXCL: C-X-C motif chemokine ligand; DOX: doxycycline; EM703: non-antibiotic derivative of erythromycin; ERK: extracellular signal-regulated kinase; ERM: erythromycin; FOM: Fosfomycin; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; H.: Haemophilus; i.b.: intrabronchially; IFN: interferon; i.n.: intranasally; iNOS: inducible NO synthase; i.p.: intraperitoneally; i.t.: intratracheal; i.v.: intravenously; IL: interleukin; JM: josamycin; JNK: c-Jun N-terminal kinase; KC: keratinocytes-derived chemokine; LVFX: levofloxacin; LPS: lipopolysaccharide; LZD: linezolid; M.: Mycoplasma; MAPK: mitogen-activated protein kinase; MCP: monocyte chemoattractant protein; MDA: malondialdehyde; MDSC: myeloid-derived suppressor cell; MIP: macrophage inflammatory protein; MLE: murine lung epithelial; MMP: matrix metalloproteinase; MODS: multi organ dysfunction syndrome; MOX: moxifloxacin; MPO: myeloperoxidase; MRSA: methicillin-resistant Staphylococcus aureus; MSSA: methicillin-sensitive S. aureus; NA: not applicable; ND: not determined; NE: neutrophil elastase; NO: nitric oxide; NLRP3: nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein-3; P.: Pseudomonas; PAF: platelet-activating factor; PBEC: primary bronchial epithelial cell; PBMC: peripheral blood mononuclear cell; PMN: polymorphonuclear neutrophils; RA: receptor antagonist; RCT: randomised controlled trial; RSV: respiratory syncytial virus; ROS: reactive oxygen species; RXM: roxithromycin; S.: Streptococcus; STAT1: signal transducer and activator of transcription 1; SMA: superior mesenteric artery; sTNFR: soluble TNF receptor; TBARS: thiobarbituric acid reactive substances; TBLN: tracheobronchial lymph nodes; TEL: telithromycin; TET: tetracycline; TGF-β1: transforming growth factor-β1; t.t.: transtracheal; TLR: Toll-like receptor; TNF-α: tumour necrosis factor-α; TREM: triggering receptor expressed on myeloid cells; VAP:ventilator-associated pneumonia; VEGF: vascular endothelial growth factor; VRE: vancomycin-resistant enterococci.