Inhibitory Effects of Surfactant Protein A on Surfactant Phospholipid Hydrolysis by Secreted Phospholipases A2

Chabot, Sophie; Koumanov, Kamen; Lambeau, Gérard; Gelb, Michael H.; Balloy, Viviane; Chignard, Michel; Whitsett, Jeffrey A.; Touqui, Lhousseine

doi:10.4049/jimmunol.171.2.995

Cited by 53 publications

(55 citation statements)

References 46 publications

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“…Further studies using site-directed mutagenesis targeting the residues in the central pore will be required to confirm this model. Recently SP-A was reported to be an endogenous inhibitor of groups IIA and X PLA 2 s (19). The inhibition of P. flavoviridis PLA 2 by SP-A was not affected by the presence of various monosaccharides (28), suggesting that the carbohydrate-binding domain of SP-A is not involved in the PLA 2 inhibition.…”

Section: Discussionmentioning

confidence: 94%

“…The M-type PLA 2 receptor is a type I transmembrane glycoprotein having a tandem repeat of eight CTLDs (16,17), and its soluble form was shown to be a mammalian endogenous PLA 2 inhibitor (18). Furthermore, SP-A was reported to have inhibitory activity against group IIA and group X PLA 2 s (19). Therefore, CTLDs might play a very important role as a common structural basis for the PLA 2 binding and inhibition.…”

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confidence: 99%

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Mapping the Region of the α-Type Phospholipase A2 Inhibitor Responsible for Its Inhibitory Activity

Okumura

Ohno

Nishida

et al. 2005

Journal of Biological Chemistry

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␣-Type phospholipase A 2 inhibitory protein (PLI␣) from the serum of the venomous snake Gloydius brevicaudus, GbPLI␣, is one of the protective endogenous proteins that neutralizes its own venom phospholipase A 2 (PLA 2 ), and it is a homotrimer of subunits having a C-type lectin-like domain. The nonvenomous snake Elaphe quadrivirgata has a homologous serum protein, EqPLI␣-LP, that does not show any inhibitory activity against various snake venom PLA 2 s (Okumura, K., Inoue, S., Ikeda, K., and Hayashi, K. (2003) IUBMB Life 55, 539 -545). By constructing GbPLI␣-Eq-PLI␣-LP chimeric proteins, we have mapped the residues important in conferring GbPLI␣ inhibitory activity on region 13-36 in the primary structure of GbPLI␣. Noninhibitory EqPLI␣-LP showed comparable inhibitory activity only when this region was replaced with that of GbPLI␣. Further, mutational analysis of the candidate residues revealed that the individual GbPLI␣ to EqPLI␣-LP residue substitutions N26K, K28E, D29N, and Y144S each produced a mutant GbPLI␣ protein with reduced inhibitory activity, with the single N26K substitution having the most significant effect. Residues 13-36 were suspected to be located in the helical neck region of the GbPLI␣ trimer. Therefore, the region of GbPLI␣ responsible for PLA 2 inhibition was distinct from the carbohydrate-binding site of the homologous C-type lectin.Phospholipases A 2 (PLA 2 s, EC 3.1.1.4) 2 catalyze the hydrolysis of the acyl-ester bond at the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. Secretory PLA 2 s are a growing family of low molecular weight, highly disulfide-linked, Ca 2ϩ -requiring secretory enzymes with a His-Asp catalytic dyad and are classified into six main groups (I, II, III, V, X, and XII) according to their primary structures (1). Snake venom is one of the most abundant sources of secretory PLA 2 s, which exhibit a wide variety of pharmacological effects including neurotoxicity and myotoxicity (2). Elapidae venom contains group I PLA 2 s, and Viperidae venom contains group II ones (3). Venomous snakes have three distinct types of PLA 2 inhibitory proteins (PLI␣, PLI␤, and PLI␥) in their blood to protect themselves from the leakage of their own venom PLA 2 s into the circulatory system (4 -6). PLI␣ has only been identified in the blood of Viperidae snakes, such as Protobothrops flavoviridis (renamed from Trimeresurus flavoviridis according to the present taxonomy) (7), Gloydius brevicaudus (renamed from Agkistrodon blomhoffii siniticus) (8), Bothrops asper (9), and Cerrophidion godmani (10). It is a 75-kDa trimeric glycoprotein of 20-kDa subunits having a C-type lectin-like domain (CTLD), which is homologous to that of collectins, such as serum mannose-binding protein (MBP) and lung surfactant-apoproteins (11). G. brevicaudus, B. asper, and C. godmani PLI␣s are composed of three identical subunits, whereas P. flavoviridis PLI␣ is a trimer of two homologous subunits. P. flavoviridis and G. brevicaudus PLI␣s inhibit specifically the group II acidic PLA 2...

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Mapping the Region of the α-Type Phospholipase A2 Inhibitor Responsible for Its Inhibitory Activity

Okumura

Ohno

Nishida

et al. 2005

Journal of Biological Chemistry

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“…Respiratory function in freely moving mice was assessed by barometric plethysmography with a whole-body plethysmograph (Buxco Electronic, Sharon, Conn.) according to the manufacturer's instructions as previously described (6). Each animal was placed in the main chamber; the difference in pressure between this chamber and a reference chamber was determined with a differential pressure transducer connected to an amplifier, and the data were recorded with BioSystem XA analyzer software (Buxco Electronic).…”

Section: Reagentsmentioning

confidence: 99%

Differences in Patterns of Infection and Inflammation for Corticosteroid Treatment and Chemotherapy in Experimental Invasive Pulmonary Aspergillosis

Huerre²,

et al. 2005

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Aspergillus fumigatus causes invasive pulmonary aspergillosis (IPA). This disease is one of the most lifethreatening opportunistic infections in immunocompromised patients. The type of immunosuppressive regimen under which IPA occurs has rarely been investigated. In this study, we evaluated various parameters of the innate immune response during the progression of murine IPA induced by the intratracheal administration of A. fumigatus conidia as a function of two immunosuppressive treatments: a corticosteroid and a chemotherapeutic agent. We compared host responses various times after infection in terms of survival, pulmonary production of pro-and anti-inflammatory cytokines, cellular trafficking in the airways, lung injury, respiratory distress, and fungal development. We found that IPA pathogenesis involved predominantly fungal development in mice treated by chemotherapy and an adverse host response in mice treated with a corticosteroid. These previously unrecognized differences should be taken into account in evaluations of the pathogenesis of IPA in animal models.Aspergillus fumigatus belongs to a family of saprophytic filamentous fungi found in most environments. It sporulates abundantly, leading to the release into the atmosphere of large quantities of conidia. A. fumigatus spreads within the environment by means of airborne conidia, and the small diameter of these spores (2 to 3 m) enables them to reach the lung alveoli (19). Pulmonary host defenses against A. fumigatus are mediated by phagocytic cells of the innate immune system. Resident alveolar macrophages are thought to eliminate conidia by phagocytosis, whereas recruited polymorphonuclear neutrophils (PMN) destroy hyphae by producing reactive oxygen species (30,34).If the immune defense system of the lung is weakened, then conidia germinate and produce hyphae that invade the surrounding lung tissues (39), leading to the development of invasive pulmonary aspergillosis (IPA). This disease is one of the most life-threatening opportunistic infections in immunocompromised patients (19), and its incidence has increased in recent decades (14, 18). This increase in incidence has been associated with an increase in the number of people at risk due to solid organ transplantation, hematopoeitic stem cell transplantation, and intensive chemotherapeutic or immunosuppressive regimens (24). Furthermore, the difficulty of diagnosing IPA early and the low efficacy of treatments result in a high rate of mortality due to this disease in immunocompromised patients (10,23).Despite the increase in the number of IPA patients, the pathogenesis of this mycosis remains poorly understood. Experimental animal models of IPA have been developed for investigation of the role of innate immunity in the progression of the disease. Various infection protocols have been used and have generated conflicting data. More importantly, the type of immunosuppressive regimen in which IPA develops has received very little attention. In this study, we investigated various parameters of the innate...

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“…34 and 35, and L. Touqui, unpublished observations). Furthermore, intratracheal instillation of sPLA 2 -IIA (50 g) has only a modest effect on surfactant phospholipid and respiratory functions in wild-type mice (21).…”

Section: Discussionmentioning

confidence: 99%

“…Broncho-alveolar lavage fluids were obtained as previously described (21). Tissue homogenates were prepared as previously described (22,23).…”

Section: Spla 2 Assaysmentioning

confidence: 99%

In Vivo Protective Role of Human Group IIA Phospholipase A2 against Experimental Anthrax

Piris-Giménez

Payá

Lambeau

et al. 2005

The Journal of Immunology

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Anthrax is an acute disease caused by Bacillus anthracis. Some animal species are relatively resistant to anthrax infection. This trait has been correlated to the extent of the local inflammatory reaction, suggesting innate immunity to be the first line of defense against B. anthracis infection in nonimmunized hosts. Group IIA secreted phospholipase A2 (sPLA2-IIA) is produced in particular by macrophages and possesses potent antibacterial activity especially against Gram-positive bacteria. We have previously shown in vitro that sPLA2-IIA kills both germinated B. anthracis spores and encapsulated bacilli. Here we show that sPLA2-IIA plays in vivo a protective role against experimental anthrax. Transgenic mice expressing human sPLA2-IIA are resistant to B. anthracis infection. In addition, in vivo administration of recombinant human sPLA2-IIA protects mice against B. anthracis infection. The protective effect was observed both with a highly virulent encapsulated nontoxinogenic strain and a wild-type encapsulated toxinogenic strain, showing that toxemia did not hinder the sPLA2-IIA-afforded protection. sPLA2-IIA, a natural component of the immune system, may thus be considered a novel therapeutic agent to be used in adjunct with current therapy for treating anthrax. Its anthracidal activity would be effective even against strains resistant to multiple antibiotics.

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Inhibitory Effects of Surfactant Protein A on Surfactant Phospholipid Hydrolysis by Secreted Phospholipases A2

Cited by 53 publications

References 46 publications

Mapping the Region of the α-Type Phospholipase A2 Inhibitor Responsible for Its Inhibitory Activity

Mapping the Region of the α-Type Phospholipase A2 Inhibitor Responsible for Its Inhibitory Activity

Differences in Patterns of Infection and Inflammation for Corticosteroid Treatment and Chemotherapy in Experimental Invasive Pulmonary Aspergillosis

In Vivo Protective Role of Human Group IIA Phospholipase A2 against Experimental Anthrax

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