Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep

Abstract

The macrophage- and monocyte-produced cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as a major mediator of endotoxin-induced injury. To determine if TNF alpha could reproduce the effects of endotoxin on the lung, we intravenously administered 10 micrograms/kg of human recombinant TNF alpha into five chronically instrumented unanesthetized sheep on two occasions to characterize the TNF alpha response and its reproducibility. We assessed changes in lung mechanics, pulmonary and systemic hemodynamics, gas exchange, and the number and type of peripheral blood leukocytes. We also determined airway reactivity by use of aerosolized histamine before and after TNF alpha infusion. Pulmonary arterial pressure (Ppa) peaked within 30 min of initiating the TNF alpha infusion [47.7 +/- 2.2 vs. 15.9 +/- 0.4 (SE) cmH2O at base line] and then returned toward base line over 4 h. There was a brief decline in left atrial pressure after TNF alpha. Pulmonary hypertension was accompanied by leukopenia, neutropenia, and increases in the alveolar-arterial O2 difference (AaDO2). Dynamic lung compliance (Cdyn) declined after TNF alpha, reaching a nadir within 15 min of the initiation of the TNF alpha infusion [0.045 +/- 0.007 vs. 0.093 +/- 0.007 (+/- SE) l/cmH2O at base line]. Resistance to airflow across the lung (RL) increased from 1.2 +/- 0.2 cmH2O.l-1.s at base line, peaking at 5.4 +/- 1.3 cmH2O.l-1.s 30 min after the start of the TNF alpha infusion. Alterations in Cdyn and RL persisted for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle.

“…In this regard, some studies have demonstrated elevated levels of various cytokines in the bronchoalveolar lavage fluid from asthmatic patients (8-10). Moreover, recent animal studies have shown that, apart from their potential role in regulating airway inflammation in the allergic state, certain cytokines (notably IL-1␤ and TNF-␣) may also contribute to the associated heightened airway constrictor responsiveness (2,6,25,27). Finally, administration of specific cytokines has been shown to induce impairment of ␤-adrenoceptor-mediated airway relaxation in the isolated guinea pig trachea (26).…”

“…In this connection, exogenous administration of TNF-␣ to animals in vivo has been shown to induce bronchial constrictor hyperresponsiveness (6,25), and treatment of isolated guinea pig airways with IL-1 ␤ or TNF-␣ has been found to reduce isoproterenol-mediated relaxation in vitro (26). Moreover, treatment of antigen-sensitized animals with an IL-1 receptor antagonist has been shown to inhibit both their in vivo bronchial hyperreactivity to histamine (2) or substance P (27), as well as the accompanying pulmonary infiltration with leukocytes, including eosinophils and neutrophils (2,27,28).…”

The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment

“…The hypothesis has been formulated on clinical criteria that, in unresolving ARDS, serious nosocomial infections, such as ventilator-associated pneumonia (VAP) amplify SIRS and lead to MODS and death [5,6,15,16]. MODS develops more frequently in patients dying with sepsis than in those dying with refractory hypoxaemia [19][20]. Progression of fibroproliferation to extensive pulmonary fibrosis directly causes respiratory death in 15-40% of ARDS patients (table 2) [7,15,17].…”

Respiratory effects of lipopolysaccharide-induced inflammatory lung injury in mice

“…Endotoxin-induced acute lung injury is also associated with respiratory mechanical changes represented by dynamic compliance reduction, and increased pulmonary resistance [12,15,19,20]. The mechanical changes have been attributed to the presence of pulmonary oedema, followed by ventilation-perfusion mismatch, or airway constriction [20].…”