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Growth Factors and Cytokines in Acute Lung Injury

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Abstract

Cytokines and growth factors play an integral role in the maintenance of immune homeostasis, the generation of protective immunity, and lung reparative processes. However, the dysregulated expression of cytokines and growth factors in response to infectious or noxious insults can initiate and perpetuate deleterious lung inflammation and fibroproliferation. In this article, we will comprehensively review the contribution of individual cytokines and growth factors and cytokine networks to key pathophysiological events in human and experimental acute lung injury (ALI), including inflammatory cell recruitment and activation, alveolar epithelial injury and repair, angiogenesis, and matrix deposition and remodeling. The application of cytokines/growth factors as prognostic indicators and therapeutic targets in human ALI is explored. © 2011 American Physiological Society. Compr Physiol 1:81‐104, 2011.

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Figure 1. Figure 1.

TNF‐α and IL‐1 signal transduction pathways and regulation by endogenous inhibitors. TNF‐α can signal through TNFR1 or TNFR2, with ligation of TNFR1 resulting in activation of inflammatory gene expression and caspase 8‐mediated apoptosis, whereas ligation of TNFR2 results in MAPK‐ and NF‐κB‐dependent inflammatory gene expression but not apoptosis pathways. Ligation of IL‐1RI in combination with the IL‐1R accessory protein (IL‐1RAcP) results in activation of MyD88‐toll signaling cascades culminating in MAPK‐ and NF‐κB‐dependent expression of inflammatory cytokines and adhesion molecules. TNF‐α bioactivity is inhibited by shed soluble TNF receptors (sTNFR), whereas IL‐1 bioactivity is inhibited by competitive binding with the IL‐1 receptor antagonist (IL‐1RA) or binding to the nonsignaling cell associated or soluble IL‐1RII.

Figure 2. Figure 2.

Schematic depicting stages of neutrophil migration and cytokines involved. Cytokines listed are stimulatory unless otherwise designated. CXCLIZ (SDF‐1) SDF‐1 promotes retention of PMN within marrow. Chemokines induce shedding of L‐selectin while promoting β‐integrin‐mediated adhesion and eventual transmigration. ¥G‐CSF induces PMN chemokinesis but not chemotaxis, whereas chemokines induce both chemokinesis and chemotaxis.

Figure 3. Figure 3.

Schematic depicting secondary structure of CXC, CC, CX3C, and C chemokines. Secondary structure is maintained by disulfide bounds between highly conserved cysteine amino acid residues.

Figure 4. Figure 4.

Schematic depicting cytokine networks that regulate inflammation during acute lung injury. Infectious or noxious insults result in activation of resident alveolar or interstitial macrophages and structural cells (alveolar epithelial cells, fibroblast) in either a pathogen recognition receptor‐dependent or cytokine‐dependent fashion, leading to the expression of effector cytokines and chemokines. The elaboration of proximal cytokines (TNF‐α, IL‐1) by lung macrophages results in a substantial amplification of cytokine/chemokine expression by structural cells in the lung microenvironment. Leukocytes recruited to the lung (e.g., PMN and exudate macrophages) express injurious cytotoxic products (e.g., reactive oxygen and nitrogen species, proteases) and molecules that induce apoptosis of alveolar epithelium (e.g., FasL, TRAIL). Late mediators of inflammation, including HMGB1 and MIF, are induced by factors released during the early phase of the host response, and reciprocally perpetuate inflammation in a TNF/IL‐1 and chemokine‐dependent fashion. Early‐response cytokines can also trigger the coagulation cascade via the production of tissue factor. The acute injury response is tightly controlled by immunoregulatory cytokines (IL‐10, IL‐13, GM‐CSF) produced by both lung myeloid and structural cells. Cytokines produced during the acute inflammatory insult also actively participate in and shape lung reparative responses (see Fig. ).

Figure 5. Figure 5.

Schematic depicting growth factors that lung injury and repair. During lung injury, various insults contribute to pulmonary endothelial and AEC necrosis and/or apoptosis. Endothelial injury is exacerbated by angiogenic factors VEGF and Ang‐2, whereas Ang‐1 and Ang‐4 prevent endothelial injury and can promote repopulation of endothelium. GM‐CSF mitigates AEC injury, and stimulates epithelial reparative responses. KGF and HGF exert similar AEC proliferative effects. Several growth factors (e.g., TGF‐β, PDGF, IGF) promote fibroblast effector responses, including myofibroblast differentiation, extracellular matrix deposition, and MMP expression. If inadequately controlled, these processes can culminate in deleterious fibroproliferation.



Figure 1.

TNF‐α and IL‐1 signal transduction pathways and regulation by endogenous inhibitors. TNF‐α can signal through TNFR1 or TNFR2, with ligation of TNFR1 resulting in activation of inflammatory gene expression and caspase 8‐mediated apoptosis, whereas ligation of TNFR2 results in MAPK‐ and NF‐κB‐dependent inflammatory gene expression but not apoptosis pathways. Ligation of IL‐1RI in combination with the IL‐1R accessory protein (IL‐1RAcP) results in activation of MyD88‐toll signaling cascades culminating in MAPK‐ and NF‐κB‐dependent expression of inflammatory cytokines and adhesion molecules. TNF‐α bioactivity is inhibited by shed soluble TNF receptors (sTNFR), whereas IL‐1 bioactivity is inhibited by competitive binding with the IL‐1 receptor antagonist (IL‐1RA) or binding to the nonsignaling cell associated or soluble IL‐1RII.



Figure 2.

Schematic depicting stages of neutrophil migration and cytokines involved. Cytokines listed are stimulatory unless otherwise designated. CXCLIZ (SDF‐1) SDF‐1 promotes retention of PMN within marrow. Chemokines induce shedding of L‐selectin while promoting β‐integrin‐mediated adhesion and eventual transmigration. ¥G‐CSF induces PMN chemokinesis but not chemotaxis, whereas chemokines induce both chemokinesis and chemotaxis.



Figure 3.

Schematic depicting secondary structure of CXC, CC, CX3C, and C chemokines. Secondary structure is maintained by disulfide bounds between highly conserved cysteine amino acid residues.



Figure 4.

Schematic depicting cytokine networks that regulate inflammation during acute lung injury. Infectious or noxious insults result in activation of resident alveolar or interstitial macrophages and structural cells (alveolar epithelial cells, fibroblast) in either a pathogen recognition receptor‐dependent or cytokine‐dependent fashion, leading to the expression of effector cytokines and chemokines. The elaboration of proximal cytokines (TNF‐α, IL‐1) by lung macrophages results in a substantial amplification of cytokine/chemokine expression by structural cells in the lung microenvironment. Leukocytes recruited to the lung (e.g., PMN and exudate macrophages) express injurious cytotoxic products (e.g., reactive oxygen and nitrogen species, proteases) and molecules that induce apoptosis of alveolar epithelium (e.g., FasL, TRAIL). Late mediators of inflammation, including HMGB1 and MIF, are induced by factors released during the early phase of the host response, and reciprocally perpetuate inflammation in a TNF/IL‐1 and chemokine‐dependent fashion. Early‐response cytokines can also trigger the coagulation cascade via the production of tissue factor. The acute injury response is tightly controlled by immunoregulatory cytokines (IL‐10, IL‐13, GM‐CSF) produced by both lung myeloid and structural cells. Cytokines produced during the acute inflammatory insult also actively participate in and shape lung reparative responses (see Fig. ).



Figure 5.

Schematic depicting growth factors that lung injury and repair. During lung injury, various insults contribute to pulmonary endothelial and AEC necrosis and/or apoptosis. Endothelial injury is exacerbated by angiogenic factors VEGF and Ang‐2, whereas Ang‐1 and Ang‐4 prevent endothelial injury and can promote repopulation of endothelium. GM‐CSF mitigates AEC injury, and stimulates epithelial reparative responses. KGF and HGF exert similar AEC proliferative effects. Several growth factors (e.g., TGF‐β, PDGF, IGF) promote fibroblast effector responses, including myofibroblast differentiation, extracellular matrix deposition, and MMP expression. If inadequately controlled, these processes can culminate in deleterious fibroproliferation.

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Jane C. Deng, Theodore J. Standiford. Growth Factors and Cytokines in Acute Lung Injury. Compr Physiol 2010, 1: 81-104. doi: 10.1002/cphy.c090011