Early disruption of the alveolar-capillary barrier in a ricin-induced ARDS mouse model: neutrophil-dependent and -independent impairment of junction proteins

Abstract

Irrespective of its diverse etiologies, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) leads to increased permeability of the alveolar-capillary barrier, which in turn promotes edema formation and respiratory failure. We investigated the mechanism of ALI/ARDS lung hyperpermeability triggered by pulmonary exposure of mice to the highly toxic plant-derived toxin ricin. One prominent hallmark of ricin-mediated pulmonary intoxication is the rapid and massive influx of neutrophils to the lungs, where they contribute to the developing inflammation yet may also cause tissue damage, thereby promoting ricin-mediated morbidity. Here we show that pulmonary exposure of mice to ricin results in the rapid diminution of the junction proteins VE-cadherin, claudin 5, and connexin 43, belonging, respectively, to the adherens, tight, and gap junction protein families. Depletion of neutrophils in ricin-intoxicated mice attenuated the damage caused to these junction proteins, alleviated pulmonary edema, and significantly postponed the time to death of the intoxicated mice. Inhibition of matrix metalloproteinase (MMP) activity recapitulated the response to neutrophil depletion observed in ricin-intoxicated mice and was associated with decreased insult to the junction proteins and alveolar-capillary barrier. However, neutrophil-mediated MMP activity was not the sole mechanism responsible for pulmonary hyperpermeability, as exemplified by the ricin-mediated disruption of claudin 18, via a neutrophil-independent mechanism involving tyrosine phosphorylation. This in-depth study of the early stage mechanisms governing pulmonary tissue integrity during ALI/ARDS is expected to facilitate the tailoring of novel therapeutic approaches for the treatment of these diseases.

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

“…The relatively modest changes in TNFA levels were surprising and may be due to its short half-life (~20 minutes) relative to the time of sample collection (i.e., 24 hours). Given the prominence of the edema and its likely role in the lethal pathogenesis of ricin toxicosis, further elucidation of the causes that may induce or exacerbate this presentation, such as the role of impairment of tight junction proteins and mast cells, may provide a novel insight to ricin immunopathogenesis (11,41).…”

“…In nonhuman primates (NHPs), inhalation of RT elicits the clinical equivalent of acute respiratory distress syndrome (ARDS), characterized by widespread apoptosis of alveolar macrophages, intraalveolar edema, neutrophilic infiltration, accumulation of proinflammatory cytokines, and fibrinous exudate (3)(4)(5). Similar effects are observed in mice, rats, and swine (6)(7)(8)(9)(10)(11). RT is derived from castor beans (Ricinus communis) and is a 65-kDa heterodimeric glycoprotein consisting of 2 subunits, RTA and RTB, joined via a single disulfide bond.…”

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

“…7,8 A precipitous decline in alveolar macrophages (AMs) occurs within hours and is accompanied by a corresponding influx of polymorphonuclear (PMN) cells. 9 Disease severity and lung permeability track with the increase of pro-inflammatory cytokines like IL-6, IL-1, and tumor necrosis factor alpha (TNF-α) in serum and bronchoalveolar lavage (BAL) fluids. [10][11][12] Local damage is further exacerbated by TNF-α and its family members like TRAIL, which render lung epithelial cells hyper-sensitive to the effects of RT, as evidenced by augmented (>300 fold) secretion of IL-6 and other proinflammatory cytokines, as well as a lower threshold to elicit PCD.…”

Study on Intervention Mechanism of Yiqi Huayu Jiedu Decoction on ARDS Based on Network Pharmacology

“…Gap junction plays an important role in the permeability of the alveolar capillary barrier. Decreasing connexins such as VE-cadherin and Caluin 5 will lead to increased permeability of the ALI/ ARDS vascular barrier, which in turn will promote edema formation and respiratory failure [61]. Blocking Ras-associated protein Rab10 can lead to reduced TLR4 expression, reduced production of inflammatory cytokines and interferons, and reduced lung injury [62].…”