\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[greek,ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Perspective: The Potential Role of Vasoactive Intestinal Peptide in
treating COVID-19}



\author[1]{Jonathan C. Javitt, MD, MPH}%
\affil[1]{Johns Hopkins University}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{Keywords}

Aviptadil, Vasoactive Intestinal Peptide, VIP, SARS-CoV-2, COVID-19,
Corona Virus, Acute Respiratory Distress Syndrome, ARDS, Acute Lung
Injury, ALI, surfactant, Alveolar Type II, ATII

\textbf{Perspective: The Potential Role of Vasoactive Intestinal Peptide
in treating COVID-19}

\textbf{Jonathan C. Javitt, MD, MPH\textsuperscript{1,2,3}}

Fifty years ago, Nature published a short report entitled ``Potent
peripheral and splanchnic vasodilator peptide from normal gut,''
published by two young scientists working at the Karolinska Institute
(Said, Mutt, 1970). Their discovery of Vasoactive Intestinal Peptide
(VIP) led to five decades of research into a potent natural
anti-cytokine that may have unique potential to block pathways of cell
death, particularly those that affect the pulmonary Alveolar Type II
cell in SARS-CoV-2 infection.

In the 100 years since the Spanish Flu caused more wartime deaths than
combat, no effective drug has been developed to prevent mortality from
viral-induced Acute Lung Injury (ALI). The primary cause of death in
COVID-19 infection is generally described as Acute Respiratory Distress
Syndrome (ARDS), caused by ALI. The injury is generally attributed to
cytokine storm -- i.e. a massive release of inflammatory cytokines as
viral particles infect and then cause rupture of pulmonary epithelium
cells. Mortality rates as high as 78\% are being reported in association
with COVID-19-related ARDS, despite mechanical ventilation and
best-available intensive care. There is increasing recognition that this
lethal pulmonary injury may be driven by loss of the surfactant that is
secreted by pulmonary alveolar type 2 cells that express Angiotensin
Converting Enzyme 2 (ACE2) surface receptors to which the SARS-CoV-2
virus binds (Mason 2020).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Our purpose is to offer a perspective on why Vasoactive Intestinal
Peptide (VIP) and future long-acting derivatives of VIP may prove to be
of therapeutic value in the arsenal of drugs currently proposed to treat
COVID-19 and subsequent corona virus outbreaks and why previous
formulation and intellectual property barriers that impeded its
commercial development may be offset by overwhelming public health need.
These topics are relevant in light of two FDA multicenter clinical
trials that have now been initiated to treat COVID-19 patients with a
formulation of Aviptadil, a synthetic form of human VIP
(www.clinicaltrials.gov NCT 04311697 and NCT 04360096). While the
perspective offered is clearly that of a commercial enterprise, the
research cited was primarily performed without industry support.

In brief, we believe that Aviptadil (a synthetic form of human VIP) may
uniquely target the pathways that are attacked by the SARS-CoV-2 virus,
resulting in Acute Lung Injury (ALI), and lead to death from Acute
Respiratory Distress Syndrome (ARDS) in COVID-19.

Research into VIP's mechanisms of action is a relic of an older era in
biology, when researchers focused on cellular pathways and genomics was
not yet a word. Although VIP was once viewed as a promising drug and
substantial resources were invested in elucidating its pharmacokinetics,
toxicology, and safety pharmacology, pharmaceutical companies found it
challenging to administer, given the need for inhaled or IV
administration and challenging to formulate. Pulmonary drugs are
notoriously difficult to develop, given regulatory requirements for
long-term inhaled toxicology studies in multiple species, including
primates (Tepper 2016). FDA has asserted that these preclinical
toxicology requirements must be observed in the case of candidate drugs
to treat COVID-19. VIP, on the other hand, completed four-species
toxicology and safety pharmacology studies in both intravenous and
inhaled dosage forms but did not proceed to the market for lack of a
compelling clinical target. Phase 2 trials in sarcoidosis (Prasse 2010),
pulmonary hypertension (Leuchte 2008), pulmonary fibrosis, and
allergy/asthma suggest that VIP has no major toxicities when inhaled at
doses of 300\selectlanguage{greek}µ\selectlanguage{english}g/day and that the toxic dose is at least 25x higher.

Vasoactive Intestinal Peptide (VIP) was first proposed as a modulator of
lung inflammation by Said (Said 1988, 1991). VIP is known to have a
beneficial effect in numerous models of lung injury (table 1) at the
above doses and has shown clinical effects in clinical trials of Acute
Respiratory Distress Syndrome (ARDS) and Sarcoid, meaningful reduction
in TNF-\selectlanguage{greek}α \selectlanguage{english}and CD4/CD8 ration was seen in sarcoid (Prasse 2010).

Table 1: Effect of VIP in experimental models of acute lung injury\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Species} & \textbf{Etiology of lung injury} &
\textbf{References}\tabularnewline
\midrule
\endhead
Rat & NDMD induced lung injury w/ arginine & Said 1996, Said \& Dickman
2000\tabularnewline
Rat & Xanthine/xanthine oxidase-induced lung injury in perfused lungs &
Berisha 1990, Misra 1990\tabularnewline
Guinea Pig & Paraquat (methyl viologen) & Pakbaz 1993, Said \& Dickman
2000\tabularnewline
Rat & Hydrochloric acid induced pulmonary edema & Foda
1988\tabularnewline
Sheep & Intravenous infusion of platelet-activating factor & Pakbaz
1988\tabularnewline
Dog & Intravenous infusion of platelet-activating factor & Pakbaz
1988\tabularnewline
Guinea Pig & Phospholipase C & Pakbaz 1991\tabularnewline
Rat & Cobra venom factor model of septic shock & Mulligan
1992\tabularnewline
\bottomrule
\end{longtable}

During the years that were invested in preclinical, particularly inhaled
toxicology studies, shifting priorities within the pharmaceutical
industry combined with lack of composition of matter patent protection
rendered VIP a less than compelling candidate for commercialization.

Until now\ldots{}

Suddenly, the human race is threatened by a pulmonic virus that attacks
the same cells in the lung that VIP uniquely supports and protects.
Multiple investigators have confirmed that the SARS-CoV family of
viruses selectively attack pulmonary Alveolar Type II (ATII) cells
because of their ACE2 receptors, in contrast to other pulmonary
epithelial cells. The ATII cells manufacture surfactant that is
essential to gas exchange in the alveolus (Mason 2020). For those who
don't think about pulmonary physiology every day, remember that
epithelial cells die almost immediately upon exposure to air. That's why
corneal abrasions occur as soon as the pre-corneal tear film is damaged
and why people who sleep with their mouths open wake up with a
``scratchy'' throat. The pulmonary epithelium is the only epithelial
surface that is constantly exposed to air. We can close our eyes and our
mouths, but not our lungs. The patency of the alveolus and the viability
of its vulnerable epithelial cells is maintained by an
aqueous/surfactant layer that enables gas exchange. However the
integrity of this layer requires a film of surfactant to maintain
surface tension.

VIP is a potent anti-cytokine in the lung that provides key defense
against numerous forms of acute lung injury. Although named (or
mis-named) for the tissue in which it was first isolated, VIP is
produced by neuroendocrine cells throughout the body and by
T-lymphocytes, B-lymphocytes, and macrophages. VIP is highly localized
in the lung (Virgolini 1995) but is a widely distributed immunomodulator
with protective effects in heart, thyroid gland, kidney, immune system,
urinary tract and genital organs. Early COVID-19 lung injury is
characterized by a remarkable degree of hypoxia in the absence of
overwhelming pneumonia, suggesting a primary injury to the pulmonary
gas-exchange mechanism. Patients frequently report ``crackling sounds''
while attempting to breath, consistent with the theory that loss of
surfactant and alveolar gas exchange is an early hallmark of COVID-19.
VIP is the body's primary defense against cytokine injury in the lung
and elsewhere. Unlike synthetic anti-cytokines, such as anti-IL6 drugs,
VIP is shown to have a specific role in preserving surfactant production
in the lung (Li 2004, Li 2010) and in protecting type 2 alveolar cells.
Accordingly, VIP and longer acting modifications of VIP have been
proposed in the past as respiratory therapeutics (Mathioudakis 2013).

As we learn more about the lethal consequences of COVID-19 infection,
cardiac and other non-pulmonary effects are increasingly reported. In
the lung, VIP attenuates, delays or prevents acute lung injury in
various experimental models of ARDS, both in isolated lungs as well as
in vivo. VIP protects the heart and other vital organs against oxidative
injury, has anti-inflammatory activity against a variety of inflammatory
mediators and is anti-apoptotic. There is ample evidence to suggest a
potential role of VIP in preventing apoptosis, reducing inflammation and
endotoxemia, and maintaining surfactant production in the face of lung
injury.

\textbf{COVID-19 and Immune Response:}

Coronavirus pathophysiology in humans has been studied since the 2004
SARS epidemic, where pulmonary complications were traced to release of
proinflammatory cytokines occurred, including IL-6, IL-12, and TNF-\selectlanguage{greek}α.
\selectlanguage{english}Patients with SARS-CoV-2 pneumonia admitted to an ICU had higher plasma
levels of cytokines including IL-6, IL-2, IL-7, IL-10,
granulocyte-colony stimulating factor (G-CSF), interferon-\selectlanguage{greek}γ-\selectlanguage{english}inducible
protein (IP10), monocyte chemoattractant protein (MCP1), macrophage
inflammatory protein 1 alpha (MIP1A), and TNF-\selectlanguage{greek}α \selectlanguage{english}(Wong 2004). Studies on
MERS-CoV, demonstrated marked upregulation of cytokine genes of IL-6,
IL-1\selectlanguage{greek}β, \selectlanguage{english}and IL-8 (Channappanaver 2017). This phenomenon is now widely
called a ``cytokine storm.'' More recent data, point to the specific
attack of the virus on ACE2 receptors of the type 2 alveolar cells with
selective death of those cells.

In recent years, interleukin 6 (IL-6) blocking drugs and biologics have
been developed to treat arthritis, inflammatory bowel disease, and other
autoimmune conditions. While some have suggested that blockade of IL-6
alone may block the cytokine storm in COVID-19, failures of IL-6
specific antagonists in recent clinical trials suggest that a broader
anti-cytokine strategy may be needed. IL-6 is only one of numerous
cytokines that are upregulated and attack the pulmonary epithelium.

If the mechanism of ALI in SARS-CoV-2 infection was driven by
cytokine-induced inflammation alone, steroids and other
anti-inflammatory drugs might be expected to have some salutary effect.
Lung injuries seen in COVID-19 are increasingly recognized as similar to
those in premature infants where loss of surfactant, secreted by
alveolar type II cells leads to demise of premature infants despite
mechanical ventilation. The SARS-CoV-2 virus is known to enter cells via
binding to ACE2 receptors on the cell surface and those receptors are
predominantly found on the Alveolar type II (ATII) cells. Moreover, VIP
receptors are preferentially expressed on ATII cells and VIP is shown to
prevent their apoptosis in models of lung injury (Onoue, 2004).

\textbf{Scientific Rationale for VIP effect in COVID-19}

\textbf{Preservation of pulmonary tissue:}

Three studies validate the protective role of VIP on isolated and
transplanted lung models. Isolated rat lungs stored in VIP- containing
solutions had significantly more normal shaped mitochondria, less
mitochondrial edema, less distortion of mitochondrial cristae, thinner
basal lamina, and less aggregation of nuclear chromatin than lungs
stored in control solutions (Alessandrini 1993). VIP significantly
delayed the onset of edematous lung injury in isolated perfused rat
lungs -- in control solution after 213 minutes, in Aviptadil solution
after 349 minutes (Pakbaz 1994). VIP was effective in preventing
ischemia-reperfusion injury in an \emph{in vivo} rat lung
transplantation model as demonstrated by improved pulmonary function
(Nagahiro 1998).

\textbf{Inhibition of Apoptosis:} One of the main features of
coronavirus lung injury is destruction of the alveolar epithelium, with
severe damage to the alveolar capillary barrier and major increase in
alveolar capillary permeability. Alveolar epithelium of patients who die
from lung injury is notable for evidence of DNA fragmentation. Extensive
alveolar epithelial cell apoptosis is found in murine models of
lipopolysaccharide-induced lung injury (Matute-Bello 2003). There are
two independent cell death pathways involved in the destruction of lung
cells in ARDS -- the Fas/Fas ligand and the perforin/granzyme system
(Hashimoto 2000). Several lines of evidence point to the Fas/Fas ligand
system as an underlying mechanism responsible for the epithelial cell
apoptosis in acute lung injury and ARDS (Albertine 2002). The Fas/Fas
ligand system is comprised of the cell membrane surface receptor Fas
(CD95) and its ligand. Alveolar and airway epithelial cells express Fas
on their surface and the expression of Fas in epithelial cells increases
in response to inflammatory mediators. Soluble Fas ligand is present in
bronchio-alveolar lavage fluids of patients with early ARDS and reaches
higher concentrations in the lung fluids of patients who die. This
detected Fas ligand is biologically active and causes apoptosis in
normal human lung epithelial cells (Matute-Bello 1999). VIP is a potent
inhibitor of Fas ligand expression and has been shown to inhibit Fas
ligand-mediated cell death (Delagado 1998,1999).

The second cell death pathway relevant to ARDS and COVID-19 lung injury
acts via degranulation of serine proteases, granzymes, together with the
pore-forming protein, perforin, to induce rapid death of the target
cells (Hashimoto 2000). VIP is a proven inhibitor of activation-induced
perforin, as well as of granzyme B and therefore actively contributes to
the reduction of deleterious proinflammatory and cell death-inducing
processes, particularly in the lungs (Sharma 2006). Caspase-3, has been
identified as a key mediator of apoptosis in mammalian cells via its
role in cleaving a variety of substrate proteins and inducing DNA
fragmentation. In animal models of ALI, caspase activity is
significantly increased compared to its activity in normal lungs and VIP
is shown to suppress caspase activation (Said \& Dickman, 2000).
Finally, NMDA induced experimental lung injury is associated with
downregulation of the anti-apoptotic gene bcl-2 and this downregulation
is reversed is preserved in lungs treated with VIP (Said \& Dickman,
2000).

\textbf{Inflammation:} During the early phase of ALI, the lung is the
site of an intense inflammatory process with sequential activation of
cytokines, chemokines, and secretion of proteases, as well as
concomitant collagen synthesis. Evidence of an acute inflammatory
reaction in the alveolar-microvascular area also includes recruitment
and activation of inflammatory cells, increased production of toxic
oxygen metabolites, nitric oxide, and a protein rich exudate in the air
spaces. A key regulator involved in a variety of these processes is the
nuclear transcription factor NF-kB. This protein is normally located in
cell cytoplasm and bound to an inhibitory protein IkB in an inactive
state. Inducers of NF-kB activation trigger a cascade of reactions
ending in liberation of NF-kB from IkB. NF-kB trans-locates into the
cell nucleus where it binds to the promoter sequences of many defense
and immune response genes thereby inducing their expression -- for
example the expression of tumor necrosis factor alpha (TNF-\selectlanguage{greek}α\selectlanguage{english}). VIP has
been shown to inhibit NF-k\texttt{}\texttt{}B activation in numerous
animal models of acute lung injury, while preventing or attenuating the
injury. Delgado 1998).

\textbf{Effect of VIP on Surfactant Production:} A pathologic hallmark
of the ALI/ARDS is the damage to the surfactant-producing alveolar type
II cells (Mossel 2008). These cells are characterized by Angiotensin
Converting Enzyme 2 (ACE2) receptors on the cell surface and, therefore,
may be particularly susceptible to SARS-CoV-2 virus infection. Studies
have demonstrated high density VIP binding sites on rat type II cells
(Onoue, 2004). Li demonstrated in rat lung explants that VIP increased
the incorporation of methyl-choline into phosphatidylcholine -- the
major component of the pulmonary surfactants -- by enhancing the
activity of the enzyme choline-phosphate cytidylyltransferase (Li 2004).
VIP upregulates C-Fos protein expression in cultured type II alveolar
cells, which is instrumental in promoting synthesis of pulmonary
surfactant phospholipids (Li 2007) and induces surfactant protein A
expression in ATII cells through activation of PKC/c-Fos pathway.

\textbf{Conclusion:}

In the 50 years that have elapsed since the discovery of VIP (Said
1970), numerous mechanisms of pulmonary protection have been elucidated
in connection with VIP and efficacy signals have been seen in
association with ARDS, Sarcoid, and perhaps other human lung conditions.
It may be that VIP has not advanced to approval as a human pulmonary
drug because of the need for either IV or inhaled administration and
because of its relatively short half-life, requiring multiple daily
doses. However, we now face a lethal viral infection that specifically
attacks the ATII cells that are essential for the continuation of human
life. Those are the cells that bind VIP and rely on VIP to drive the
production of surfactant. This highly specific role of VIP in the lung
may be key to combating the lethal effects of SARS-CoV-2 infection.
Unlike synthetic anti-cytokine and interleukin drugs, VIP has no known
human toxicity,. COVID-19 may represent a unique circumstance in which
the biologic potential of VIP offsets any challenges to its route or
frequency of administration, its commercial attractiveness (or lack
thereof) due to lack of patent protection, and its remarkably low cost
compared to more ``modern'' drugs.

Illustration credit: Nicol\selectlanguage{ngerman}ás Fernández

\textbf{Acknowledgement}

The author acknowledges the scientific input of Yves Sagot, PhD, Norman
B. Javitt, PhD, MD, and Matthew J. Javitt, MD, in the preparation of
this work.

\textbf{Author Affiliations:}

1. CEO, NeuroRx, Inc., Radnor, PA

2. Adj. Professor, Johns Hopkins School of Medicine, Baltimore, MD

3. Senior Fellow, National Security Health Policy Center, Potomac
Institute for Policy Studies, Arlington, VA

\textbf{Disclosure:}

The author is an employee and shareholder of a company that is
developing VIP for commercial use.

\subsection*{References}

{\label{references}}

Albertine, KH, Soulier MF, Wang Z, et. al. Fas and Fas Ligand Are
Up-Regulated in Pulmonary Edema Fluid and Lung Tissue of Patients With
Acute Lung Injury and the Acute Respiratory Distress Syndrome. Am J
Pathol 2002;161(5):1783-1796.

Alessandrini, F., Thakkar, M., Foda, H.D., Said, S.I., Lodi, R., Pakbaz,
H., and Schraufnagel, D.E. Vasoactive intestinal peptide enhances lung
preservation. Transplantation 1993;56:964-973.

Berisha, H., Foda, H., Sakakibara, H., Trotz, M., Pakbaz, H., and Said,
S.I. Vasoactive intestinal peptide prevents lung injury due to
xanthine/xanthine oxidase. Am. J. Physiol 1990;259:L151-L155.

Channapanaver R, Perlman S. Pathogenic human coronavirus infections:
Causes and consequences of cytokine storm and immunopathology. Semin
Immunopathol 2017;39(5):529-539.

Delgado, M, Martinez C, Pozo D, Calvo JR, Leceta J, Ganea D, Gomariz RP.
Vasoactive intestinal peptide (VIP) and pituitary adenylate
cyclase-activation polypeptide (PACAP) protect mice from lethal
endotoxemia through the inhibition of TNF-alpha and IL-6. J Immunol.
1999;162:1200-1205.

Delgado M, Munoz-Elias EJ, Kan Y, Gozes I, Fridkin M, Brenneman DE,
Gomariz RP, Ganea D. Vasoactive intestinal peptide and pituitary
adenylate cyclase-activating polypeptide inhibit tumor necrosis factor
alpha transcriptional activation by regulating nuclear factor-kB and
cAMP response element-binding protein/c-Jun. J. Biol. Chem.
1998;273:31427-31436.

FDA Guidance for Industry: COVID-19 Public Health Emergency: General
considerations for Pre-IND meeting requests for COVID-19 related drugs
and biological products. May 2020

Foda, H.D., Iwanaga, T., Liu, L.-W., and Said, S.I. Vasoactive
intestinal peptide protects against HCl-induced pulmonary edema in rats.
Ann NY Acad Sci 1988;633-636.

Hashimoto S, Kobayashi A, Kooguchi K, et. al. Upregulation of two death
pathways of perforin/granzyme and FasL/Fas in spetic acute respiratory
distress syndrome. Am J Respir Crit Care Med 2000, 161(1):237-243.

Leuchte HH, Baezner C, Baumgartner RA, et. al. Inhalation of vasoactive
intestinal peptide in pulmonary hypertension. Eur Respir J
2008;32:1289-1294.

Li, L., Luo, Z.Q., Zhou, et. al. Effect of vasoactive intestinal peptide
on pulmonary surfactants phospholipid synthesis in lung explants. Acta
Pharmacol. Sin. 2004;25:1652-1658.

Li L, She H, Yue S, et. al. Role of C-Fos gene in vasoactive intestinal
peptide promoted synthesis of pulmonary surfactant phospholipids. Regul
Pept 2007;140(3):117-124.

Li L, Hua S, Yue S, Luo Z, et. al., Vasoactive intestinal polypeptide
induces surfactant protein A expression in ATII cells through activation
of PKC/c-Fos pathway. Peptides 2010;31(11):2016-2051

Mason R. Pathogenesis of COVID-19 from a cell biologic perspective. Eur
Respir J. April 9 Epub ahead of print.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144II60/

Mathioudakis AG, Chatzimavridou-Grigoriadou V, Evangelopoulou E,
Mathioudakis GA. Vasoactive Intestinal Peptide Inhaled Agonists:
Potential Role in Respiratory Therapeutics. Hippokratia 2013;17(1):12-16

Matute-Bello G,~Liles WC,~Steinberg KP,~Kiener PA,~Mongovin S,~Chi
EY,~Jonas M,~Martin TR. Soluble Fas ligand induces epithelial cell
apoptosis in humans with acute lung injury (ARDS). J Immunol
1999;163(4):2217-2225.

Matute-Bello G, Martin T. Science Review: Apoptosis in acute lung
injury. Crit Care 2003;7(5):355-358

Misra BR and Misra HP. Vasoactive intestinal peptide, a singlet oxygen
quencher. J. Biol. Chem 1990;265:15371-15374.

Mossel EC, Wang J, Jeffers S, et al. SARS-CoV replicates in primary
human alveolar type II cell cultures but not in type I-like cells.
Virology 2008;372:127-135.

Mulligan MS, Varani J, Warren JS, Till, G.O., Smith, C.W., Anderson,
D.C., Todd, R.F., III, and Ward, P.A. Roles of beta 2 integrins of rat
neutrophils in complement- and oxygen radical-mediated acute
inflammatory injury. J. Immunol. 1992;148:1847-1857.

Nagahiro I, Yano M, Boasquevisque CH, Fujino, S, Cooper, JD, and
Patterson, GA. Vasoactive intestinal peptide ameliorates reperfusion
injury in rat lung transplantation. J. Heart Lung Transplant.
1998;17:617-621.

Onoue S, Ohmori Y, Endo K, Yamada S, Kimura R, Yajima T. Vasoactive
intestinal peptide and pituitary adenylate cyclase-activating
polypeptide attenuate the cigarette smoke extract-induced apoptotic
death of rat alveolar L2 cells. Eur. J. Biochem. 2004;271: 1757-1767.

Pakbaz H, Berisha H, Sharaf H, Foda HD, Said SI. VIP enhances and nitric
oxide synthase inhibitor reduces survival of rat lungs perfused ex vivo.
Ann. N. Y. Acad. Sci. 1994;723:426-428.

Pakbaz H, Foda HD, Berisha HI, Trotz, M, Said SI. Paraquat-induced lung
injury: prevention by vasoactive intestinal peptide and related peptide
helodermin. Am. J. Physiol 1993;265:L369-L373.

Prasse A, Zissel G, Lützen N, Schupp J, Schmiedlin R, Gonzalez-Rey E,
Rensing-Ehl A, Bacher G, Cavalli V, Bevec D, Delgado M, Müller-Quernheim
J.. Inhaled vasoactive intestinal peptide exerts immunoregulatory
effects in sarcoidosis. Am J Respir Crit Care Med. 2010;182:540-8

Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank
K, Funk GC, Hamilton G, Novotny C, Burian B, Block LH. Vasoactive
intestinal peptide as a new drug for treatment of primary pulmonary
hypertension. J. Clin. Invest 2003;111:1339-1346.

Said SI, Mutt V. Potent peripheral and splanchnic vasodilator peptide
from normal gut. Nature. 1970; 225: 863-864.

Said SI. Vasoactive intestinal peptide in the lung. Ann NY Acad Sci
1988;527:450-464

Said SI. VIP as a modulatory of lung inflammation and airway
constriction Am Rev Respir Dis 1991;143:S22-S24.

Said SI, Dickman KG. Pathways of inflammation and cell death in the
lung: modulation by vasoactive intestinal peptide. Regul. Pept.
2000;93:21-29.

Sharma V, Delgado M, Ganea D. Granzyme B, a new player in
activation-induced cell death is downregulated by vasoactive intestinal
peptide in Th2 but not Th1 effectors. J Immunol 2006;176(1):97-110.

Tepper JS. Symposium Summary: Breathe In, Breath Out, It's Easy. What
you need to know about developing inhaled drugs. Int J Toxicol,
35(4):376-392

Virgolini I, Kurtaran A, Raderer M, et. al. Vasoactive Intestinal
Peptide Receptor Scintigraphy. J Nucl Med 1995:36(10):1732-1739

Wong CK, Lam CWK, Wu AK, et al. Plasma inflammatory cytokines in severe
acute respiratory syndrome. Clin Exp Immunol 2004:136(1):95-103.

\selectlanguage{english}
\FloatBarrier
\end{document}

