Endotoxin-induced changes in expression of surfactant proteins are dependent on the degree of lung maturity

Väyrynen, Outi; Glumoff, Virpi; Kangas, Tiina; Hallman, Mikko

doi:10.1203/00006450-199906000-00072

Cited by 3 publications

(3 citation statements)

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“…In these cases, the initial acute phase response was deficient (18,19). These data are supported by deficient responsiveness of the immature lung to LPS in vitro and an increase in the pulmonary LPS responsiveness toward term (20). Investigation of the genes and gene products responsible for deficient primary inflammatory response would help in the design of new strategies for prevention of life-threatening infections and inflammatory diseases.…”

Section: Discussionmentioning

confidence: 56%

Ontogeny of Toll-Like Receptors Tlr2 and Tlr4 in Mice

2001

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Toll-like receptors (Tlr) have recently been linked to the immunostimulatory function of microbial toxins in human and mice. Tlr signals activation of nuclear factor B that leads to the production of a number of proinflammatory mediators. Tlr4 mediates the endotoxin-induced inflammatory response, whereas Tlr2 may be involved in the response to yeast and Gram-positive bacterial products. To better understand age-related changes in acute inflammatory response, we studied the ontogeny of Tlr2 and Tlr4 mRNA in murine fetal lung, liver, and placenta by quantitative reverse transcriptase-PCR. Different expression patterns were seen between the tissues and between the Tlr. This is in accordance with the evidence that there are differences in the receptors for different microbial toxins and that the response is organ specific. We additionally show that the expression of Tlr was dependent on the stage of differentiation. In the liver, the levels of Tlr2 and Tlr4 were high regardless of the age. In the lung, Tlr2 and Tlr4 expression levels were barely detectable in immature fetus (d 14 -15). Tlr2 and Tlr4 were increased severalfold during prenatal development and further increased after birth. The present results support the finding of a deficient inflammatory response of the immature lung to microbial toxins. Bacterial LPS (also known as endotoxin) as a constituent of the cell wall of Gram-negative bacteria is a major causative agent of septic shock. LPS starts a complex cascade of events in responsive cells, particularly in monocytes and macrophages, that leads to the production of endogenous mediators such as proinflammatory cytokines IL-1, tumor necrosis factor-␣, IL-6, IL-8, and a number of other mediators. In Grampositive bacteria, the major immunostimulatory components of the cell wall include peptidoglycan and lipoteichoic acid (1, 2).A cell membrane component required for LPS-induced immunostimulation was recently identified to be a Tlr (3-5). According to the latest studies, Tlr2 and Tlr4 recognize different bacterial cell wall components. Tlr4 has been shown to mediate LPS-induced signal transduction (6, 7), whereas Tlr2 may mediate the response to yeast and Gram-positive bacteria (2, 8). Macrophages contain a surface protein called CD14, which binds ligands such as LPS (5, 7). However, CD14 does not participate directly in signaling. Rather, Tlr are essential for the innate immune response. Whereas the extracellular domain of Tlr, compatible with CD14, discriminates between pathogens, the cytoplasmic tail of Tlr triggers the cascade of intracellular mediators, leading to the activation of the nuclear factor B and of the inflammatory response. Tlr are the mammalian homologues of the Drosophila Toll family that controls the dorsoventral patterning in the developing embryo and the antimicrobial response in the adult fly (9). So far, at least six of Tlr Drosophila have been identified in humans and mice (10). It has been proposed that Tlr control the switch from the innate to adaptive immune response (11). Tlr2 an...

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Section: Discussionmentioning

confidence: 56%

Ontogeny of Toll-Like Receptors Tlr2 and Tlr4 in Mice

2001

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“…In very immature lung in vitro, the effects of proinflammatory cytokines and anti-inflammatory agents on the expression of alveolar surfactant proteins are different. Neither TNF-a nor LPS had a detectable effect on SP-A, -B, or C, whereas IL-I induced SP-A and -B, and moderately increased SP-C [35]. The switch from the IL-I-triggered induction of SP-A and SP-B to the IL-I-induced suppression of SP-B and SP-C took place at the same stage of fetal development than the onset of TNF-a-and LPS-induced suppression of SPs.…”

Section: Towards Understanding the Function Of Proinflammatory Cytokinesmentioning

confidence: 79%

“…The response elicited by the cytokines is strictly dependent on the host. In explants from near term fetal or postnatal lung, IL-l and TNF-a additively inhibited the expression of SP-A, -B and -C. LPS that induces IL-l and TNF-a in monocyte/macrophages, strongly inhibited the expression of SPs [35]. Dexam-ethasone (Dex 10-7 -10-9 M) acutely decreased the inhibitory effect of IL-I and TNF-a [36].…”

Section: Towards Understanding the Function Of Proinflammatory Cytokinesmentioning

confidence: 99%

Alveolar Surfactant and Inflammatory Mediators

Hallman¹

2000

Anesthesia, Pain, Intensive Care and Emergency Medicine — A.P.I.C.E.

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Alveolar surfactant is a lipid protein complex that prevents atelectasis, decreases work of breathing, and promotes uniform expansion of alveoli allowing efficient gas exchange. In addition, the surfactant protects the alveoli and the small airways against edema and mechanical trauma. Surfactant also contains components that are involved in defense against microbes and xenobiotics. According to present hypothesis non-clonal innate immunity -an ancient non-vertebrate defense system -is important in host defense particularly in trans cellular spaces. This system has evolved to function in a natural state of infectious and inflammatory diseases. The present methods of intensive care have been developed in the absence of the knowledge of the function of the host defense system. It is conceivable that the new and effective invasive treatment practices "fool" the innate immunity to trigger an inappropriate response that becomes destructive rather than protective to the host.The surfactant system is of central importance in pulmonary gas exchange and important in pulmonary innate immunity. Investigation on the roles of inflammatory mediators may reveal new concepts of lung protection during intensive treatment.

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